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Emerging evidence for the roles of peptide in hypertrophic scar
Life Sciences 241 (2020) 117174
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Review article
Emerging evidence for the roles of peptide in hypertrophic scar a
a,⁎
b,⁎
Jiajun Song , Xue Li , Jingyun Li
T
a
Department of Dermatology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), 123rd Tianfei Street, Mochou Road, Nanjing 210004, China Nanjing Maternal and Child Health Medical Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), 123rd Tianfei Street, Mochou Road, Nanjing 210004, China
b
ARTICLE INFO
ABSTRACT
Keywords: Peptide Hypertrophic scar TGF-β Fibroblast Collagen Inflammation Renin angiotensin system Gap junction Amine
Hypertrophic scar is a dermal fibroproliferative disorder characterized by excess collagen deposition. There are many existing treatment modalities, but none works perfectly in all individuals. Recently, evidence is increasing that peptides can play crucial roles in the prevention or treatment of hypertrophic scar. The peptides may be derived from growth factors, hormones, and intracellular products of proteolysis. In vitro and in vivo studies have revealed that a number of peptides, usually topically applied, have beneficial effects on fibroblasts in rat, mouse, hamster, pig and rabbit scar models. The length of such peptides typically ranges between 10 and 15 amino acids (aa). Peptides may reduce scar progenitors, prevent excessive scarring, decrease scar growth, speed re-epithelialization and promote scar maturation through multiple mechanisms. They may target TGF-β signaling, fibroblast function or collagen modulation, inflammation, renin angiotensin system, gap junction and other pathways. However, there is a paucity of evidence regarding specific binding sites for these peptides in scar models. Here, we review current research progress on the roles of peptides and underlying mechanisms in hypertrophic scar. We also discuss the clinical potential of peptides as therapeutic agents in scarring. Finally, the functions of several peptide-related compounds in hypertrophic scar are summarized.
1. Introduction Hypertrophic scar has a complex pathogenesis and is primarily associated with dermal fibroproliferative disorders including excessive fibroblast proliferation and abnormal collagen deposition [1]. Hypertrophic scars are limited to the original wound site and may partially regress after initial quick growth [2]. These scars often significantly affect patients' quality of life by causing functional, psychosocial, and aesthetic distress. Numerous treatments are available, including cryotherapy, dressings, intralesional corticosteroid injections, surgical removal, and laser therapy [3]. Unfortunately, treatment remains challenging due to low treatment efficacy and high recurrence rates. Recently, many studies have shown that some peptides (defined as molecules containing fewer than 50 amino acids [4]) have protective effects on wound healing and reduce scar formation. So far, 239 ther-
apeutic peptides and proteins have been approved by US-FDA for clinical use [5]. In the market, 60 peptide-based drugs have been developed, and more than 80 peptides are being evaluated in clinical trials [6]. Additionally, endogenous peptides of 3–50 aa are naturally produced by cells [7]. They have attracted tremendous attention through functioning as growth factors, peptide hormones, neuropeptides, and intracellular products of proteolysis. Currently, peptides are widely used for therapy of infectious diseases, diabetes, cancer and many other disorders [5]. However, their roles in hypertrophic scar are not well known. In this review, we summarize the emerging evidence regarding the roles and function mechanisms of peptides in hypertrophic scar. We also describe the clinical potential of therapeutic peptide use for scar and related disorders. Moreover, the roles of peptide-related compounds especially amines in hypertrophic scar are presented.
Abbreviations: TGF-β, transforming growth factor-β; P144, Peptide 144; rLMWP-EGF, recombinant low molecular weight protamine-EGF; GHRP-6, growth hormone-releasing peptide 6; PGE1, Prostaglandin E1; RAS, renin-angiotensin system; NorLeu3-A(1-7), NorLeu3-angiotensin(1-7); BNP, brain natriuretic peptide; C15, chemerin15; WP, Whey peptides; cav-1p, caveolin-1 cell-permeable peptide; AEEA, amine N-(2-aminoethyl) ethanolamine; FTY720, 2-amino-2-[2-(4-octylphenyl)]1, 3-propanediol hydrochloride; OxProp, oxandrolone and propranolol; LCB 03-0110, (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol ⁎ Corresponding authors. E-mail addresses: [email protected] (X. Li), [email protected] (J. Li). https://doi.org/10.1016/j.lfs.2019.117174 Received 6 November 2019; Received in revised form 11 December 2019; Accepted 12 December 2019 Available online 13 December 2019 0024-3205/ © 2019 Elsevier Inc. All rights reserved.
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2. Roles of peptides in hypertrophic scar and underlying mechanisms
2.2. Peptide hormones Peptide hormones play crucial roles in the human endocrine system. In the field of pathological scars, several peptide hormones play significant roles. One example is E4, a peptide which originates from endostatin (amino acids 133–180). It was found that E4 prevented TGF-βinduced dermal fibrosis in a mouse model and in human skin [16]. Another example is growth hormone-releasing peptide 6 (GHRP-6), a short hexapeptide (HWAWFK) that acts as a ghrelin-like GH secretagogue. It has been shown to prevent the onset of hypertrophic scar in rabbits, although it failed to significantly reverse mature hypertrophic scar [17]. The mechanism may be that GHRP-6 binds to CD36 receptor to activate peroxisome proliferator-activated receptor gamma (PPARγ) and then reduces TGF-β1 and CTGF expression to ameliorate fibrosis [18]. The safety and efficacy of GHRP-6 were reported in clinical practice in obese patients to have only minor adverse events [19]. However, its possible application to treatment of fibrosis in humans needs further exploration. Prostaglandin E1 (PGE1), a potent vasodilator, activates the prostaglandin E1 (EP) receptor. It has been used therapeutically in several diseases [20,21]. PGE1 can prevent hypertrophic scar formation by increasing type I collagenase activity and IL-8 production [22]. Moreover, a recent study showed that a lipid-encapsulated preparation of PGE1, Lipo-PGE1, suppresses collagen production through the ERK/Ets1 signaling pathway [23]. Inhibition of the renin-angiotensin system (RAS) by an angiotensinconverting enzyme inhibitor has shown beneficial effects on fibrotic pathologies [24]. The angiotensin analogue NorLeu3-angiotensin(1-7) (NorLeu3-A(1-7)) accelerates healing, reduces fibrotic scar, and normalizes tissue architecture in rats or diabetic mice [25]. Angiotensin AT receptor is involved in NorLeu3-A(1-7) function. Through targeting of RAS, NorLeu3-A(1-7) also accelerates full-thickness corneal wound healing in rabbits [26]. Finally, it inhibits scar formation in the rat fullthickness incision injury model [27]. Mechanisms of action include inducing progenitor proliferation, accelerating vascularization, re-epithelialization and collagen deposition [28].
Increasing evidence suggests that peptides have beneficial effects on scar fibroblasts and in animal models of scarring. Over the past few decades, many peptides regulating pathological processes in hypertrophic scar have been identified (Fig. 1). Information on peptide characteristic, application protocols, outcomes, and peptide target pathways are summarized in Table 1. 2.1. Growth factor related peptides Growth factors such as transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) play crucial roles in regulating a host of cellular processes including cellular proliferation, growth, healing, and cellular differentiation [8]. In hypertrophic scar, TGF-β is particularly significant. Its receptors are overexpressed [9], and it displays a diversity of profibrotic effects in fibroblasts. Inhibition of the TGF-β signaling pathway can be used to alleviate scarring. A novel pegylated peptide antagonist of TGF-β1 (25 amino acids, human TGF-β1 41st to 65th residues) developed by Huang et al. [10] blocks TGF-β function by competing with ligands for binding to the TGF-β receptor. This TGF-β antagonist peptide was reported to speed re-epithelialization and reduce scarring in the setting of partial thickness porcine burns [11]. It also inhibited the fibrotic phenotype in the human hypertrophic scar fibroblasts [12]. Peptide 144 (P144®; Digna Biotech., Spain), which is the acetic salt of a 14mer peptide derived from human TGF-β1 type III receptor/betaglycan 730–743, also inhibits TGF-β and thereby reduces scarring in the human hypertrophic scar nude mouse model [13]. P144 prevents the interaction between TGF-β1 and the TGF-β1 type III receptor, thus blocking the TGF-β signaling pathway. Finally, injection of TGF-β3 reduces fibronectin and collagen deposition and improves neodermal architecture and reduces scarring [14]. The 53 aa polypeptide EGF can accelerate epidermal and mesenchymal regeneration, cellular proliferation, and cell motility. Interestingly, recombinant low molecular weight protamine-EGF (rLMWP-EGF) acts as a novel therapeutic drug for topical burn wound healing with no obvious toxic effect [15]. Thus, EGF functions by targeting fibroblast function and could be an alternative approach for scar therapeutics.
2.3. Neuropeptides Neuropeptides are used by neurons to communicate with one other. Many neuropeptides are involved in a wide range of brain functions. Brain natriuretic peptide (32 aa, ~3 kDa), reduces scar formation in the heart [29]. In the rat incision model, brain natriuretic peptide (BNP) treatment decreased the number of scars; the mechanism may have been by blocking TGF-β signaling [30]. Another neuropeptide, substance P, is a neurotransmitter and neuromodulator whose endogenous receptor is the neurokinin 1 receptor. Substance P is elevated in human hypertrophic scar tissues, modulates the expression of apoptosis-associated genes, and participates in pathological scar formation [31]. Therefore, substance P functions by targeting fibroblast apoptosis-related processes and contributes to scar formation. 2.4. Peptides from products of proteolysis A variety of peptides are derived from the enzymatic degradation of proteins [32,33]. Tri-peptide GHK, released during extracellular matrix protein degradation, is involved in skin regeneration via multiple cellular pathways [34]. GHK and its copper complex decrease IGF-2-dependent TGF-β1 secretion [35]. Through promotion of cell proliferation and angiogenesis, GHK-Cu-liposomes could retard scar formation in mice [36]. Thymosin β4, a naturally occurring peptide, plays crucial roles in the regeneration and repair of injured cells and tissues [37]. Thymosin β4 also decreases scar formation and fibrosis through reducing the number of myofibroblasts.
Fig. 1. Summary of peptides that targeting multiple pathways involved in hypertrophic scar. Anta. means antagonist. 2
3
TGF-β anta. peptide
P144
TGF-β3 rLMWP-EGF
E4
GHRP6
PGE1
Lipo-PGE1
NorLeu3-A(1-7)
BNP
Substance P
GHK
Thymosin β4
cP12
C15 Whey peptides
LYENRL
Heparinmimetic peptide
DS-SILY
N2
αCT1 peptide
Cav-1p
AZX100
Ultrashort peptide
1
2
3 4
5
6
7
8
9
10
11
12
13
14
15 16
17
18
19
20
21
22
23
24
ILVAGK, LIVAGK, 6
YARAAARQARAWLRRAS*APLPGLK, 24, a phosphopeptide analogue of HSP20
RQIKIWFQNRRMKWKKDGIWKASFTTFTVTKYWFYR, 36, cav-1 scaffolding domain
RQPKIWFPNRRKPWKKRPRPDDLEI, 25
LMKNMDPLNDNV, 12, hinge region of nonmuscle myosin heavy chain II
Dermatan sulfate -RRANAALKAGELYKSILYGC, 20
VVAGEGDKS, 9
LYENRL
AGEDPHGYFLPGQFA, 15 Whey proteins were digested by protease
PSHISKYILRWRPK, 14
SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES, 43
GHK, 3, liver cell growth factor
Substance P
SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH, 32
DRVYIHP, 7, analogue of an angiotensin peptide
A lipid microsphere-incorporated prostaglandin E1
Prostaglandin E1
HWAWFK, 6
Endostatin 133–180 (SYCETWRTEAPSATGQASSLLGGRLLGQSAASCHHAYIVLCIENSFMT)
Recombinant TGF-β3 expressed in NIH 3 T3 cells Expression plasmid containing LMWP-EGF in Escherichia coli
TSLDASIIWAMMQN, 14, human TGFR-III 730–743
VKRKRIEAIRGQILSKLRLASPPSQ, 25, human TGF-β1 41–65
Peptide characteristic
anta.: antagonist; S*denotes phosphoserine; NR, not reported.
Peptide
No.
Table 1 Peptide therapy evaluated, application protocols, main outcome and target pathway.
Injected
Injected Topical treatment
Topical treatment
Topical treatment; 48 h, 72 h treatment
Application
Human keloid fibroblasts; Siberian hamster scarring model Rat incision model
Swine model of partial thickness burn Mouse and pig incisional wounds Hypertrophic scar fibroblasts
Full-thickness mice model, BALB/c mice, dorsal burn injury model Rat incision model
Porcine burn injury model, porcine hot comb model Mice incision model Rats caesarean section wounds Hypertrophic scar fibroblasts
Full-thickness excision model in rats, diabetic mice; Wild strain Sprague-Dawley rats Normal, hypertrophic scar, and keloid skin fibroblasts Normal human dermal fibroblasts cells Rat incision model
Topical use
Injected
0–48 h treatment
Pluronic gel
Hyaluronic acid vehicle Intravenously
Topical treatment Intragastrically administered Treatment for 24 h, 48 h Hydrogel
Infused
Injected
Treatment
24 h treatment
Topically, systemically Injected
Subcutaneous injections Normal and hypertrophic scar 72 h treatment skin fibroblasts Human dermal fibroblasts 24 h treatment
Domestic pigs, partial thickness burns model; Human HS-derived fibroblasts Human scar transplanted to BALB/c-nu/nu T-deficient nude mice Sprague-Dawley rats Laser induced burn wound mice Ex vivo human abdominal skin model; 6-to 8-week-old C57BL/6 J male mice New Zealand male rabbits
Model
Fibroblast function or collagen modulation Fibroblast function or collagen modulation Inflammation pathway Others
Fibroblast function or collagen modulation TGF-β1/Smad pathway
TGF-β1/Smad pathway
Fibroblast function or collagen modulation Fibroblast function or collagen modulation RAS pathway
TGF-β1/Smad pathway
TGF-β1/Smad pathway Fibroblast function or collagen modulation TGF-β1/Smad pathway
TGF-β1/Smad pathway
TGF-β1/Smad pathway
Peptide target pathway
Inhibit TGF-β1-stimulated Smad2 phosphorylation, nuclear translocation of Smad2/3 Reduce TGF-β1-induced CTGF expression, improve collagen organization Promote epithelial and dermal regeneration
Inhibit MMP mediated collagen degradation, reduce dermal scarring Block a specific inflammatory pathway Reduce scar progenitor
Others
Fibroblast function or collagen modulation
TGF-β1/Smad pathway
Gap junction
Fibroblast function or collagen modulation Inflammation pathway
Prevent activation of hypertrophic TGF-β1/Smad pathway scar derived fibroblasts Produce newly formed blood vessels, Fibroblast function or increase re-epithelialization collagen modulation
Promote wound fibroblast proliferation and inhibit apoptosis Decrease IGF-2-dependent TGF-β1 secretion Mature earlier and heal with minimal scaring Increase re-epithelialization and reduce scarring Reduce scarring Lead to smaller scar width
Prevent the onset of hypertrophic scar Increase type I collagenase activity and IL-8 production Suppresses collagen production via the ERK/Ets-1 signaling pathway Accelerate healing, reduce fibrotic scar Reduce apparent scars
Reduce scarring Show improved burn wound healing efficacy Reverse TGF-β-induced fibrosis in human and mouse skin
Promote scar maturation, decrease collagen I expression
Reduce scar formation; Reduce collagen I, III expression
Main outcome
[65]
[63,64]
[61,62]
[56–59]
[54]
[53]
[51,52]
[48]
[43,44] [46]
[38–41]
[37]
[34–36]
[31]
[30]
[25,27]
[23]
[22]
[17–19]
[16]
[14] [15]
[13]
[10–12]
Ref.
J. Song, et al.
Life Sciences 241 (2020) 117174
Life Sciences 241 (2020) 117174
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The fibronectin-derived peptide P12 can speed healing and reduce scarring by limiting burn injury progression [38]. The mechanism may be that fibronectin peptides bind platelet derived growth factor BB (PDGF-BB) and enhance its functionality, thereby promoting the survival of human dermal fibroblasts [39]. In the porcine burn injury model, the cyclized version of fibronectin-derived peptides, cP12, reduced blood vessel occlusion and ultimately reduced scarring [38]. As a new class of peptides, fibronectin-derived epiviosamines including P12 (epiviosamine-1) and P46 can also both reduce blood vessel occlusion and reduce scarring [40,41]. The scarring process begins with inflammation [42]. Peptides targeting the inflammation pathway can therefore be useful drugs for scar treatment. Resolution mediator chemerin15 (C15), a 15aa peptide derived from cleavage of chemerin, inhibits inflammation through the G protein-coupled receptor ChemR23 and accelerates re-epithelialization on keratinocytes, thereby reducing scarring by reprograming the wound microenvironment [43,44]. Whey peptides (WP) are derived from the digestion of whey proteins by protease. Most commonly, WP exhibit multiple actions including antioxidant, antihypertension, anti-diabetes, and anti-obesity with a variety of underlying mechanisms [45]. In rats following caesarean section, WP treatment resulted in smaller skin scar width on day 7 [46]. WP's function mechanism in reducing scar may be related to its multitarget therapy properties. Recently, we conducted a comparative peptidomic analysis to identify significantly changed peptides in human hypertrophic scar tissue [47]. One of the endogenous peptides, LYENRL, prevented hypertrophic scar-derived fibroblast activation by inhibiting the TGF-β1/ Smad pathway [48]. We believe that other endogenous peptides identified in this peptidomic analysis may also significantly inhibit fibroblast proliferation, decrease collagen expression and reduce scarring.
Other important cell permeant phosphopeptide analogue of HSP20, AZX100, could significantly improve collagen organization and prevent excessive scarring [63]. Additionally, upon entering cells AZX100 is associated with lipid rafts and increases phospho-caveolin (Y14) expression [64]. Possibly through enhancement of tissue regeneration, two ultrashort peptide hydrogel candidates (self-assembling peptide hydrogels) may accelerate burn wound healing, and possibly inhibit scar formation [65]. 3. Clinical studies involving peptides Since the early 1980s, 239 US FDA-approved therapeutic peptides and proteins have become available for clinical use [5]. Here, we briefly summarize recent progress and the prospect of selected peptide-based therapeutics in clinical trials (Table 2) for treatment of scars and related disorders [66–84]. A total of 79 interventional or observational studies were found for “Hypertrophic Scar” on US National Library of Medicine/ClinicalTrials. gov website on November 27, 2019. Those studies included fractional laser, topical corticosteroid, Botox, and silicone gel intervention methods. Only a few peptide-related therapeutics in hypertrophic scar that have reached phase I/II clinical trials. One is STP705/Cotsiranib, which is composed of siRNA oligonucleotides and histidine-lysine copolymer (HKP) peptide (siRNA:peptide at a 1:4 mass ratio) [66]. STP705 inhibited expression of fibrosis-related genes including α-SMA, Col1A1, and Col3A1, suggesting its potential for broad application in many fibrotic diseases. Another is scar-related peptide P144, which can also reduce scarring and has completed phase I clinical trials in healthy volunteers [69]. A synthetic peptide from human lactoferrin, PXL01, has completed phase I/II clinical trials in surgical adhesions [67,68]. Several scar-related peptides have reached clinical development in other diseases, including BNP/nesiritide for cardiovascular diseases [70–72], LipoPGE1/alprostadil for diabetic nephropathy and ischemic heart disease [73,74], as well as prostaglandin E1 for head and neck microsurgery, cervical ripening, and hypoxemic respiratory failure in term newborns [79–81]. For patients with diabetic foot ulcers, NorLeu3-A(1-7)/ DSC127 [75] and Granexin gel/aCT1 peptide [76] have entered phase II and III clinical trials, respectively.
2.5. Mimetic peptides Mimetic peptides have gained an abundance of uses in divergent fields [49,50]. Heparin mimetic peptide nanofiber gels are able to prevent scar formation by mediating wound contraction [51]. The mechanism may be associated with supporting tissue neovascularization and enhancing collagen deposition [52]. Other peptides, such as DS-SILY, a decorin mimetic and a collagen-binding peptidoglycan, may reduce dermal scarring through MMP mediated collagen degradation [53]. Additionally, administration of a synthetic peptide N2 (which mimics the binding region of non-muscle myosin heavy chain with IgM) decreases dermal injury through blocking a specific inflammatory pathway and increasing re-epithelization [54]. In hypertrophic scarring, fibroblast activity can be induced by mast cells via gap junction communication [55]. Thus, targeting the gap junction could be used to cure scars. The connexin43 mimetic peptide αCT1 promotes regenerative healing of wounds and reduces scar progenitor [56]. Multiple preclinical and clinical studies have been conducted with αCT1 in wound healing, scar, heart, eye, brain, or lungs [57]. In cutaneous scarring, a phase II clinical trial demonstrated that αCT1 treatment led to a 47% improvement in scar scores compared to controls [58]. Other studies have shown that the mode of action of αCT1 involves reduced interaction of Cx43/ZO-1 and gap junction size remodeling [59], as well as promotion of phosphorylation of Cx43 at its serine 368 residue [59,60].
4. Other compounds related to peptides in hypertrophic scar Other peptide-related compounds, such as the aliphatic amine N-(2aminoethyl) ethanolamine (AEEA) and its analogs may inhibit hypertrophic scar development by modulating collagen metabolism [85]. Putrescine (fibrostat) belongs to the polyamines, formed by putrefaction from the decarboxylation of arginine and ornithine, which could inhibit cross-linking of type III procollagen. There was a phase II double-blind crossover study for putrescine in treatment of hypertrophic scars [86]. With no toxic effects in patients, fibrostat is suggested as a safe therapeutic agent for treatment of hypertrophic scar. The sphingosine 1-phosphate (S1P) antagonist 2-amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), acting as an immunomodulator, has been approved for treatment of multiple sclerosis. It was reported to significantly reduce cell viability and to suppress expressions of α-SMA, collagen I, and collagen III in hypertrophic scar fibroblasts and in a rabbit hypertrophic scar model [87]. Other compounds including verapamil [88], oxandrolone and propranolol (OxProp) [89], as well as succinyl hydroxamates [90] and (3(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino) phenol (LCB 03-0110) [91] have been found to suppresses scar formation and have potential as an anti-scarring agent.
2.6. Others As a fusion peptide [61], the caveolin-1 cell-permeable peptide (cav-1p) was reported to inhibit Smad2 phosphorylation, and to thereby suppress the nuclear translocation of Smad proteins (Smad2 and Smad3) in hypertrophic scar fibroblasts via reduction in TGF-β receptor type I levels [62]. 4
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J. Song, et al.
Table 2 Selected list of peptide-based therapeutics in clinical trials. Name
Type of peptide
Administration route
Target diseases
Phase, status
Trial ID
STP705/Cotsiranib PXL01
siRNA:peptide Synthetic peptide from human lactoferrin
Hypertrophic scar Surgical adhesions Post-surgery adhesion formation
I/II, unknown* II, completed I, completed
NCT02956317 [66] NCT01022242 [67] NCT00860080 [68]
P144 cream
A 14mer peptide from betaglycan Recombinant human brain natriuretic peptide B-type natriuretic peptide
Intra-dermal injection Administered locally Abdominal subcutaneous injection Topical route
Healthy volunteers
I, completed
NCT00656825 [69]
Continuous infusion
II/III, unknown* I/II, completed
NCT01941576 [70]
III, unknown*
NCT00110201 [72]
IV, completed IV, unknown*
NCT02628106 [73] NCT03159559 [74]
II, completed
NCT00796744 [75]
III, recruiting I, completed I, completed IV, unknown*
NCT02667327 NCT02652754 NCT02652572 NCT00733434
II, withdrawn
NCT00598429 [80]
NA, completed IV, recruiting I, completed I, unknown*
NCT02574338 NCT03738878 NCT01280149 NCT02820558
rhBNP
Lipo-PGE1/alprostadil
Lipo-prostaglandin e1
Intravenous injection
NorLeu3-A(1-7)/ DSC127 Granexin gel/aCT1 peptide
Norleu3-A(1-7) in a gel formulation aCT1 peptide
Topical gel route
Congenital heart defects Tetralogy of fallot Congestive heart failure Cardiomyopathy Cardiovascular disease Acute renal failure death Diabetic nephropathy Coronary microvascular perfusion in patients with ischemic heart disease Diabetic foot ulcers
Topical gel application
Diabetic foot ulcers
Prostaglandin E1
Prostaglandin E1
Continuous intravenous infusion Via nebulizer
BNP/nesiritide
Subcutaneous injection Prophylactic use
Substance P
Substance P
Venous leg ulcer Head and neck microsurgery Hypoxemic respiratory failure in term newborns Cervical ripening and induction of labor Hypertension Seasonal allergic rhinitis Diabetes mellitus, type 1
Intravaginal Intra-arterial Injections Intra-celiac artery, single treatment
NCT00252187 [71]
[76] [77] [78] [79]
[81] [82] [83] [84]
unknown*: Study has passed its completion date and status has not been verified in more than two years. Study was previously marked as Recruiting. NA, not applicable.
5. Conclusion
Acknowledgement
Hypertrophic scar remains a major challenge in medicine and causes significant morbidity. To date, silicone-containing gel dressings, laser, corticoids injection, and surgery removal have been reported to be effective alternative treatments for hypertrophic scar. In this review, we summarized the recent understanding of the roles of peptides in hypertrophic scar. Taken together, in vitro experiments generally evaluated the effects of peptides in normal skin and hypertrophic scar fibroblasts (Table 1). The majority of animal experiments analyzed the roles of peptides in rats, mice, rabbits, and pigs with burn injury or incisions. The number of amino acids for most of these peptides ranged from 10 to 15 aa. Most were applied topically. We analyzed those peptides by dividing them according to their possible targeting pathways including TGF-β signaling, fibroblast function or collagen modulation, inflammation, RAS, gap junction and other pathways as summarized in Fig. 1 and Table 1. Clinical trials of peptide-based therapeutics revealed that P144 has great potential for scar therapy (Table 2). Although numerous scar-related peptides are used in clinical trials for other diseases, there is a need for randomized controlled clinical trials supporting the efficacy of peptides in treating scar. Furthermore, a number of peptide-related compounds have been explored to suppress scar, yet the mechanism of action of these compounds still needs much further study. Although the prospects for peptide therapy in scar are bright, there is too little evidence regarding specific binding sites for those peptides in scar model. We hope that this review will be a foundation for future studies and highlight the importance of peptides for scar therapy.
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Declaration of competing interest The authors declare that they have no conflict of interests.
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Life Sciences journal homepage: www.elsevier.com/locate/lifescie
Review article
Emerging evidence for the roles of peptide in hypertrophic scar a
a,⁎
b,⁎
Jiajun Song , Xue Li , Jingyun Li
T
a
Department of Dermatology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), 123rd Tianfei Street, Mochou Road, Nanjing 210004, China Nanjing Maternal and Child Health Medical Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), 123rd Tianfei Street, Mochou Road, Nanjing 210004, China
b
ARTICLE INFO
ABSTRACT
Keywords: Peptide Hypertrophic scar TGF-β Fibroblast Collagen Inflammation Renin angiotensin system Gap junction Amine
Hypertrophic scar is a dermal fibroproliferative disorder characterized by excess collagen deposition. There are many existing treatment modalities, but none works perfectly in all individuals. Recently, evidence is increasing that peptides can play crucial roles in the prevention or treatment of hypertrophic scar. The peptides may be derived from growth factors, hormones, and intracellular products of proteolysis. In vitro and in vivo studies have revealed that a number of peptides, usually topically applied, have beneficial effects on fibroblasts in rat, mouse, hamster, pig and rabbit scar models. The length of such peptides typically ranges between 10 and 15 amino acids (aa). Peptides may reduce scar progenitors, prevent excessive scarring, decrease scar growth, speed re-epithelialization and promote scar maturation through multiple mechanisms. They may target TGF-β signaling, fibroblast function or collagen modulation, inflammation, renin angiotensin system, gap junction and other pathways. However, there is a paucity of evidence regarding specific binding sites for these peptides in scar models. Here, we review current research progress on the roles of peptides and underlying mechanisms in hypertrophic scar. We also discuss the clinical potential of peptides as therapeutic agents in scarring. Finally, the functions of several peptide-related compounds in hypertrophic scar are summarized.
1. Introduction Hypertrophic scar has a complex pathogenesis and is primarily associated with dermal fibroproliferative disorders including excessive fibroblast proliferation and abnormal collagen deposition [1]. Hypertrophic scars are limited to the original wound site and may partially regress after initial quick growth [2]. These scars often significantly affect patients' quality of life by causing functional, psychosocial, and aesthetic distress. Numerous treatments are available, including cryotherapy, dressings, intralesional corticosteroid injections, surgical removal, and laser therapy [3]. Unfortunately, treatment remains challenging due to low treatment efficacy and high recurrence rates. Recently, many studies have shown that some peptides (defined as molecules containing fewer than 50 amino acids [4]) have protective effects on wound healing and reduce scar formation. So far, 239 ther-
apeutic peptides and proteins have been approved by US-FDA for clinical use [5]. In the market, 60 peptide-based drugs have been developed, and more than 80 peptides are being evaluated in clinical trials [6]. Additionally, endogenous peptides of 3–50 aa are naturally produced by cells [7]. They have attracted tremendous attention through functioning as growth factors, peptide hormones, neuropeptides, and intracellular products of proteolysis. Currently, peptides are widely used for therapy of infectious diseases, diabetes, cancer and many other disorders [5]. However, their roles in hypertrophic scar are not well known. In this review, we summarize the emerging evidence regarding the roles and function mechanisms of peptides in hypertrophic scar. We also describe the clinical potential of therapeutic peptide use for scar and related disorders. Moreover, the roles of peptide-related compounds especially amines in hypertrophic scar are presented.
Abbreviations: TGF-β, transforming growth factor-β; P144, Peptide 144; rLMWP-EGF, recombinant low molecular weight protamine-EGF; GHRP-6, growth hormone-releasing peptide 6; PGE1, Prostaglandin E1; RAS, renin-angiotensin system; NorLeu3-A(1-7), NorLeu3-angiotensin(1-7); BNP, brain natriuretic peptide; C15, chemerin15; WP, Whey peptides; cav-1p, caveolin-1 cell-permeable peptide; AEEA, amine N-(2-aminoethyl) ethanolamine; FTY720, 2-amino-2-[2-(4-octylphenyl)]1, 3-propanediol hydrochloride; OxProp, oxandrolone and propranolol; LCB 03-0110, (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol ⁎ Corresponding authors. E-mail addresses: [email protected] (X. Li), [email protected] (J. Li). https://doi.org/10.1016/j.lfs.2019.117174 Received 6 November 2019; Received in revised form 11 December 2019; Accepted 12 December 2019 Available online 13 December 2019 0024-3205/ © 2019 Elsevier Inc. All rights reserved.
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2. Roles of peptides in hypertrophic scar and underlying mechanisms
2.2. Peptide hormones Peptide hormones play crucial roles in the human endocrine system. In the field of pathological scars, several peptide hormones play significant roles. One example is E4, a peptide which originates from endostatin (amino acids 133–180). It was found that E4 prevented TGF-βinduced dermal fibrosis in a mouse model and in human skin [16]. Another example is growth hormone-releasing peptide 6 (GHRP-6), a short hexapeptide (HWAWFK) that acts as a ghrelin-like GH secretagogue. It has been shown to prevent the onset of hypertrophic scar in rabbits, although it failed to significantly reverse mature hypertrophic scar [17]. The mechanism may be that GHRP-6 binds to CD36 receptor to activate peroxisome proliferator-activated receptor gamma (PPARγ) and then reduces TGF-β1 and CTGF expression to ameliorate fibrosis [18]. The safety and efficacy of GHRP-6 were reported in clinical practice in obese patients to have only minor adverse events [19]. However, its possible application to treatment of fibrosis in humans needs further exploration. Prostaglandin E1 (PGE1), a potent vasodilator, activates the prostaglandin E1 (EP) receptor. It has been used therapeutically in several diseases [20,21]. PGE1 can prevent hypertrophic scar formation by increasing type I collagenase activity and IL-8 production [22]. Moreover, a recent study showed that a lipid-encapsulated preparation of PGE1, Lipo-PGE1, suppresses collagen production through the ERK/Ets1 signaling pathway [23]. Inhibition of the renin-angiotensin system (RAS) by an angiotensinconverting enzyme inhibitor has shown beneficial effects on fibrotic pathologies [24]. The angiotensin analogue NorLeu3-angiotensin(1-7) (NorLeu3-A(1-7)) accelerates healing, reduces fibrotic scar, and normalizes tissue architecture in rats or diabetic mice [25]. Angiotensin AT receptor is involved in NorLeu3-A(1-7) function. Through targeting of RAS, NorLeu3-A(1-7) also accelerates full-thickness corneal wound healing in rabbits [26]. Finally, it inhibits scar formation in the rat fullthickness incision injury model [27]. Mechanisms of action include inducing progenitor proliferation, accelerating vascularization, re-epithelialization and collagen deposition [28].
Increasing evidence suggests that peptides have beneficial effects on scar fibroblasts and in animal models of scarring. Over the past few decades, many peptides regulating pathological processes in hypertrophic scar have been identified (Fig. 1). Information on peptide characteristic, application protocols, outcomes, and peptide target pathways are summarized in Table 1. 2.1. Growth factor related peptides Growth factors such as transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) play crucial roles in regulating a host of cellular processes including cellular proliferation, growth, healing, and cellular differentiation [8]. In hypertrophic scar, TGF-β is particularly significant. Its receptors are overexpressed [9], and it displays a diversity of profibrotic effects in fibroblasts. Inhibition of the TGF-β signaling pathway can be used to alleviate scarring. A novel pegylated peptide antagonist of TGF-β1 (25 amino acids, human TGF-β1 41st to 65th residues) developed by Huang et al. [10] blocks TGF-β function by competing with ligands for binding to the TGF-β receptor. This TGF-β antagonist peptide was reported to speed re-epithelialization and reduce scarring in the setting of partial thickness porcine burns [11]. It also inhibited the fibrotic phenotype in the human hypertrophic scar fibroblasts [12]. Peptide 144 (P144®; Digna Biotech., Spain), which is the acetic salt of a 14mer peptide derived from human TGF-β1 type III receptor/betaglycan 730–743, also inhibits TGF-β and thereby reduces scarring in the human hypertrophic scar nude mouse model [13]. P144 prevents the interaction between TGF-β1 and the TGF-β1 type III receptor, thus blocking the TGF-β signaling pathway. Finally, injection of TGF-β3 reduces fibronectin and collagen deposition and improves neodermal architecture and reduces scarring [14]. The 53 aa polypeptide EGF can accelerate epidermal and mesenchymal regeneration, cellular proliferation, and cell motility. Interestingly, recombinant low molecular weight protamine-EGF (rLMWP-EGF) acts as a novel therapeutic drug for topical burn wound healing with no obvious toxic effect [15]. Thus, EGF functions by targeting fibroblast function and could be an alternative approach for scar therapeutics.
2.3. Neuropeptides Neuropeptides are used by neurons to communicate with one other. Many neuropeptides are involved in a wide range of brain functions. Brain natriuretic peptide (32 aa, ~3 kDa), reduces scar formation in the heart [29]. In the rat incision model, brain natriuretic peptide (BNP) treatment decreased the number of scars; the mechanism may have been by blocking TGF-β signaling [30]. Another neuropeptide, substance P, is a neurotransmitter and neuromodulator whose endogenous receptor is the neurokinin 1 receptor. Substance P is elevated in human hypertrophic scar tissues, modulates the expression of apoptosis-associated genes, and participates in pathological scar formation [31]. Therefore, substance P functions by targeting fibroblast apoptosis-related processes and contributes to scar formation. 2.4. Peptides from products of proteolysis A variety of peptides are derived from the enzymatic degradation of proteins [32,33]. Tri-peptide GHK, released during extracellular matrix protein degradation, is involved in skin regeneration via multiple cellular pathways [34]. GHK and its copper complex decrease IGF-2-dependent TGF-β1 secretion [35]. Through promotion of cell proliferation and angiogenesis, GHK-Cu-liposomes could retard scar formation in mice [36]. Thymosin β4, a naturally occurring peptide, plays crucial roles in the regeneration and repair of injured cells and tissues [37]. Thymosin β4 also decreases scar formation and fibrosis through reducing the number of myofibroblasts.
Fig. 1. Summary of peptides that targeting multiple pathways involved in hypertrophic scar. Anta. means antagonist. 2
3
TGF-β anta. peptide
P144
TGF-β3 rLMWP-EGF
E4
GHRP6
PGE1
Lipo-PGE1
NorLeu3-A(1-7)
BNP
Substance P
GHK
Thymosin β4
cP12
C15 Whey peptides
LYENRL
Heparinmimetic peptide
DS-SILY
N2
αCT1 peptide
Cav-1p
AZX100
Ultrashort peptide
1
2
3 4
5
6
7
8
9
10
11
12
13
14
15 16
17
18
19
20
21
22
23
24
ILVAGK, LIVAGK, 6
YARAAARQARAWLRRAS*APLPGLK, 24, a phosphopeptide analogue of HSP20
RQIKIWFQNRRMKWKKDGIWKASFTTFTVTKYWFYR, 36, cav-1 scaffolding domain
RQPKIWFPNRRKPWKKRPRPDDLEI, 25
LMKNMDPLNDNV, 12, hinge region of nonmuscle myosin heavy chain II
Dermatan sulfate -RRANAALKAGELYKSILYGC, 20
VVAGEGDKS, 9
LYENRL
AGEDPHGYFLPGQFA, 15 Whey proteins were digested by protease
PSHISKYILRWRPK, 14
SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES, 43
GHK, 3, liver cell growth factor
Substance P
SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH, 32
DRVYIHP, 7, analogue of an angiotensin peptide
A lipid microsphere-incorporated prostaglandin E1
Prostaglandin E1
HWAWFK, 6
Endostatin 133–180 (SYCETWRTEAPSATGQASSLLGGRLLGQSAASCHHAYIVLCIENSFMT)
Recombinant TGF-β3 expressed in NIH 3 T3 cells Expression plasmid containing LMWP-EGF in Escherichia coli
TSLDASIIWAMMQN, 14, human TGFR-III 730–743
VKRKRIEAIRGQILSKLRLASPPSQ, 25, human TGF-β1 41–65
Peptide characteristic
anta.: antagonist; S*denotes phosphoserine; NR, not reported.
Peptide
No.
Table 1 Peptide therapy evaluated, application protocols, main outcome and target pathway.
Injected
Injected Topical treatment
Topical treatment
Topical treatment; 48 h, 72 h treatment
Application
Human keloid fibroblasts; Siberian hamster scarring model Rat incision model
Swine model of partial thickness burn Mouse and pig incisional wounds Hypertrophic scar fibroblasts
Full-thickness mice model, BALB/c mice, dorsal burn injury model Rat incision model
Porcine burn injury model, porcine hot comb model Mice incision model Rats caesarean section wounds Hypertrophic scar fibroblasts
Full-thickness excision model in rats, diabetic mice; Wild strain Sprague-Dawley rats Normal, hypertrophic scar, and keloid skin fibroblasts Normal human dermal fibroblasts cells Rat incision model
Topical use
Injected
0–48 h treatment
Pluronic gel
Hyaluronic acid vehicle Intravenously
Topical treatment Intragastrically administered Treatment for 24 h, 48 h Hydrogel
Infused
Injected
Treatment
24 h treatment
Topically, systemically Injected
Subcutaneous injections Normal and hypertrophic scar 72 h treatment skin fibroblasts Human dermal fibroblasts 24 h treatment
Domestic pigs, partial thickness burns model; Human HS-derived fibroblasts Human scar transplanted to BALB/c-nu/nu T-deficient nude mice Sprague-Dawley rats Laser induced burn wound mice Ex vivo human abdominal skin model; 6-to 8-week-old C57BL/6 J male mice New Zealand male rabbits
Model
Fibroblast function or collagen modulation Fibroblast function or collagen modulation Inflammation pathway Others
Fibroblast function or collagen modulation TGF-β1/Smad pathway
TGF-β1/Smad pathway
Fibroblast function or collagen modulation Fibroblast function or collagen modulation RAS pathway
TGF-β1/Smad pathway
TGF-β1/Smad pathway Fibroblast function or collagen modulation TGF-β1/Smad pathway
TGF-β1/Smad pathway
TGF-β1/Smad pathway
Peptide target pathway
Inhibit TGF-β1-stimulated Smad2 phosphorylation, nuclear translocation of Smad2/3 Reduce TGF-β1-induced CTGF expression, improve collagen organization Promote epithelial and dermal regeneration
Inhibit MMP mediated collagen degradation, reduce dermal scarring Block a specific inflammatory pathway Reduce scar progenitor
Others
Fibroblast function or collagen modulation
TGF-β1/Smad pathway
Gap junction
Fibroblast function or collagen modulation Inflammation pathway
Prevent activation of hypertrophic TGF-β1/Smad pathway scar derived fibroblasts Produce newly formed blood vessels, Fibroblast function or increase re-epithelialization collagen modulation
Promote wound fibroblast proliferation and inhibit apoptosis Decrease IGF-2-dependent TGF-β1 secretion Mature earlier and heal with minimal scaring Increase re-epithelialization and reduce scarring Reduce scarring Lead to smaller scar width
Prevent the onset of hypertrophic scar Increase type I collagenase activity and IL-8 production Suppresses collagen production via the ERK/Ets-1 signaling pathway Accelerate healing, reduce fibrotic scar Reduce apparent scars
Reduce scarring Show improved burn wound healing efficacy Reverse TGF-β-induced fibrosis in human and mouse skin
Promote scar maturation, decrease collagen I expression
Reduce scar formation; Reduce collagen I, III expression
Main outcome
[65]
[63,64]
[61,62]
[56–59]
[54]
[53]
[51,52]
[48]
[43,44] [46]
[38–41]
[37]
[34–36]
[31]
[30]
[25,27]
[23]
[22]
[17–19]
[16]
[14] [15]
[13]
[10–12]
Ref.
J. Song, et al.
Life Sciences 241 (2020) 117174
Life Sciences 241 (2020) 117174
J. Song, et al.
The fibronectin-derived peptide P12 can speed healing and reduce scarring by limiting burn injury progression [38]. The mechanism may be that fibronectin peptides bind platelet derived growth factor BB (PDGF-BB) and enhance its functionality, thereby promoting the survival of human dermal fibroblasts [39]. In the porcine burn injury model, the cyclized version of fibronectin-derived peptides, cP12, reduced blood vessel occlusion and ultimately reduced scarring [38]. As a new class of peptides, fibronectin-derived epiviosamines including P12 (epiviosamine-1) and P46 can also both reduce blood vessel occlusion and reduce scarring [40,41]. The scarring process begins with inflammation [42]. Peptides targeting the inflammation pathway can therefore be useful drugs for scar treatment. Resolution mediator chemerin15 (C15), a 15aa peptide derived from cleavage of chemerin, inhibits inflammation through the G protein-coupled receptor ChemR23 and accelerates re-epithelialization on keratinocytes, thereby reducing scarring by reprograming the wound microenvironment [43,44]. Whey peptides (WP) are derived from the digestion of whey proteins by protease. Most commonly, WP exhibit multiple actions including antioxidant, antihypertension, anti-diabetes, and anti-obesity with a variety of underlying mechanisms [45]. In rats following caesarean section, WP treatment resulted in smaller skin scar width on day 7 [46]. WP's function mechanism in reducing scar may be related to its multitarget therapy properties. Recently, we conducted a comparative peptidomic analysis to identify significantly changed peptides in human hypertrophic scar tissue [47]. One of the endogenous peptides, LYENRL, prevented hypertrophic scar-derived fibroblast activation by inhibiting the TGF-β1/ Smad pathway [48]. We believe that other endogenous peptides identified in this peptidomic analysis may also significantly inhibit fibroblast proliferation, decrease collagen expression and reduce scarring.
Other important cell permeant phosphopeptide analogue of HSP20, AZX100, could significantly improve collagen organization and prevent excessive scarring [63]. Additionally, upon entering cells AZX100 is associated with lipid rafts and increases phospho-caveolin (Y14) expression [64]. Possibly through enhancement of tissue regeneration, two ultrashort peptide hydrogel candidates (self-assembling peptide hydrogels) may accelerate burn wound healing, and possibly inhibit scar formation [65]. 3. Clinical studies involving peptides Since the early 1980s, 239 US FDA-approved therapeutic peptides and proteins have become available for clinical use [5]. Here, we briefly summarize recent progress and the prospect of selected peptide-based therapeutics in clinical trials (Table 2) for treatment of scars and related disorders [66–84]. A total of 79 interventional or observational studies were found for “Hypertrophic Scar” on US National Library of Medicine/ClinicalTrials. gov website on November 27, 2019. Those studies included fractional laser, topical corticosteroid, Botox, and silicone gel intervention methods. Only a few peptide-related therapeutics in hypertrophic scar that have reached phase I/II clinical trials. One is STP705/Cotsiranib, which is composed of siRNA oligonucleotides and histidine-lysine copolymer (HKP) peptide (siRNA:peptide at a 1:4 mass ratio) [66]. STP705 inhibited expression of fibrosis-related genes including α-SMA, Col1A1, and Col3A1, suggesting its potential for broad application in many fibrotic diseases. Another is scar-related peptide P144, which can also reduce scarring and has completed phase I clinical trials in healthy volunteers [69]. A synthetic peptide from human lactoferrin, PXL01, has completed phase I/II clinical trials in surgical adhesions [67,68]. Several scar-related peptides have reached clinical development in other diseases, including BNP/nesiritide for cardiovascular diseases [70–72], LipoPGE1/alprostadil for diabetic nephropathy and ischemic heart disease [73,74], as well as prostaglandin E1 for head and neck microsurgery, cervical ripening, and hypoxemic respiratory failure in term newborns [79–81]. For patients with diabetic foot ulcers, NorLeu3-A(1-7)/ DSC127 [75] and Granexin gel/aCT1 peptide [76] have entered phase II and III clinical trials, respectively.
2.5. Mimetic peptides Mimetic peptides have gained an abundance of uses in divergent fields [49,50]. Heparin mimetic peptide nanofiber gels are able to prevent scar formation by mediating wound contraction [51]. The mechanism may be associated with supporting tissue neovascularization and enhancing collagen deposition [52]. Other peptides, such as DS-SILY, a decorin mimetic and a collagen-binding peptidoglycan, may reduce dermal scarring through MMP mediated collagen degradation [53]. Additionally, administration of a synthetic peptide N2 (which mimics the binding region of non-muscle myosin heavy chain with IgM) decreases dermal injury through blocking a specific inflammatory pathway and increasing re-epithelization [54]. In hypertrophic scarring, fibroblast activity can be induced by mast cells via gap junction communication [55]. Thus, targeting the gap junction could be used to cure scars. The connexin43 mimetic peptide αCT1 promotes regenerative healing of wounds and reduces scar progenitor [56]. Multiple preclinical and clinical studies have been conducted with αCT1 in wound healing, scar, heart, eye, brain, or lungs [57]. In cutaneous scarring, a phase II clinical trial demonstrated that αCT1 treatment led to a 47% improvement in scar scores compared to controls [58]. Other studies have shown that the mode of action of αCT1 involves reduced interaction of Cx43/ZO-1 and gap junction size remodeling [59], as well as promotion of phosphorylation of Cx43 at its serine 368 residue [59,60].
4. Other compounds related to peptides in hypertrophic scar Other peptide-related compounds, such as the aliphatic amine N-(2aminoethyl) ethanolamine (AEEA) and its analogs may inhibit hypertrophic scar development by modulating collagen metabolism [85]. Putrescine (fibrostat) belongs to the polyamines, formed by putrefaction from the decarboxylation of arginine and ornithine, which could inhibit cross-linking of type III procollagen. There was a phase II double-blind crossover study for putrescine in treatment of hypertrophic scars [86]. With no toxic effects in patients, fibrostat is suggested as a safe therapeutic agent for treatment of hypertrophic scar. The sphingosine 1-phosphate (S1P) antagonist 2-amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), acting as an immunomodulator, has been approved for treatment of multiple sclerosis. It was reported to significantly reduce cell viability and to suppress expressions of α-SMA, collagen I, and collagen III in hypertrophic scar fibroblasts and in a rabbit hypertrophic scar model [87]. Other compounds including verapamil [88], oxandrolone and propranolol (OxProp) [89], as well as succinyl hydroxamates [90] and (3(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino) phenol (LCB 03-0110) [91] have been found to suppresses scar formation and have potential as an anti-scarring agent.
2.6. Others As a fusion peptide [61], the caveolin-1 cell-permeable peptide (cav-1p) was reported to inhibit Smad2 phosphorylation, and to thereby suppress the nuclear translocation of Smad proteins (Smad2 and Smad3) in hypertrophic scar fibroblasts via reduction in TGF-β receptor type I levels [62]. 4
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Table 2 Selected list of peptide-based therapeutics in clinical trials. Name
Type of peptide
Administration route
Target diseases
Phase, status
Trial ID
STP705/Cotsiranib PXL01
siRNA:peptide Synthetic peptide from human lactoferrin
Hypertrophic scar Surgical adhesions Post-surgery adhesion formation
I/II, unknown* II, completed I, completed
NCT02956317 [66] NCT01022242 [67] NCT00860080 [68]
P144 cream
A 14mer peptide from betaglycan Recombinant human brain natriuretic peptide B-type natriuretic peptide
Intra-dermal injection Administered locally Abdominal subcutaneous injection Topical route
Healthy volunteers
I, completed
NCT00656825 [69]
Continuous infusion
II/III, unknown* I/II, completed
NCT01941576 [70]
III, unknown*
NCT00110201 [72]
IV, completed IV, unknown*
NCT02628106 [73] NCT03159559 [74]
II, completed
NCT00796744 [75]
III, recruiting I, completed I, completed IV, unknown*
NCT02667327 NCT02652754 NCT02652572 NCT00733434
II, withdrawn
NCT00598429 [80]
NA, completed IV, recruiting I, completed I, unknown*
NCT02574338 NCT03738878 NCT01280149 NCT02820558
rhBNP
Lipo-PGE1/alprostadil
Lipo-prostaglandin e1
Intravenous injection
NorLeu3-A(1-7)/ DSC127 Granexin gel/aCT1 peptide
Norleu3-A(1-7) in a gel formulation aCT1 peptide
Topical gel route
Congenital heart defects Tetralogy of fallot Congestive heart failure Cardiomyopathy Cardiovascular disease Acute renal failure death Diabetic nephropathy Coronary microvascular perfusion in patients with ischemic heart disease Diabetic foot ulcers
Topical gel application
Diabetic foot ulcers
Prostaglandin E1
Prostaglandin E1
Continuous intravenous infusion Via nebulizer
BNP/nesiritide
Subcutaneous injection Prophylactic use
Substance P
Substance P
Venous leg ulcer Head and neck microsurgery Hypoxemic respiratory failure in term newborns Cervical ripening and induction of labor Hypertension Seasonal allergic rhinitis Diabetes mellitus, type 1
Intravaginal Intra-arterial Injections Intra-celiac artery, single treatment
NCT00252187 [71]
[76] [77] [78] [79]
[81] [82] [83] [84]
unknown*: Study has passed its completion date and status has not been verified in more than two years. Study was previously marked as Recruiting. NA, not applicable.
5. Conclusion
Acknowledgement
Hypertrophic scar remains a major challenge in medicine and causes significant morbidity. To date, silicone-containing gel dressings, laser, corticoids injection, and surgery removal have been reported to be effective alternative treatments for hypertrophic scar. In this review, we summarized the recent understanding of the roles of peptides in hypertrophic scar. Taken together, in vitro experiments generally evaluated the effects of peptides in normal skin and hypertrophic scar fibroblasts (Table 1). The majority of animal experiments analyzed the roles of peptides in rats, mice, rabbits, and pigs with burn injury or incisions. The number of amino acids for most of these peptides ranged from 10 to 15 aa. Most were applied topically. We analyzed those peptides by dividing them according to their possible targeting pathways including TGF-β signaling, fibroblast function or collagen modulation, inflammation, RAS, gap junction and other pathways as summarized in Fig. 1 and Table 1. Clinical trials of peptide-based therapeutics revealed that P144 has great potential for scar therapy (Table 2). Although numerous scar-related peptides are used in clinical trials for other diseases, there is a need for randomized controlled clinical trials supporting the efficacy of peptides in treating scar. Furthermore, a number of peptide-related compounds have been explored to suppress scar, yet the mechanism of action of these compounds still needs much further study. Although the prospects for peptide therapy in scar are bright, there is too little evidence regarding specific binding sites for those peptides in scar model. We hope that this review will be a foundation for future studies and highlight the importance of peptides for scar therapy.
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Declaration of competing interest The authors declare that they have no conflict of interests.
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