How does zinc modify the common cold? Clinical observations and implications regarding mechanisms of action

Medical Hypotheses (1996) 46, 295-302 © Pearson Professional Ltd 1996

How Does Zinc Modify the Common Cold? Clinical Observations and Implications Regarding Mechanisms of Action S. G. NOVICK*, J. C. GODFREY t, N. J. GODFREY t and H. R. WILDER* *Department of Chemistry, Hofstra University, Hempstead, NY 11500-1090, t Godfrey Science and Design, Inc., Huntingdon Valley, PA 19006 and ~St John Fisher College, Rochester, NY 14618, USA (Correspondence to SGN, Department of Chemistry, 135 Hofstra University, Hempstead, NY 11550-1090, USA. Teh (516) 463-5540; Fax: (516) 463-4848)

Abstract - - Clinical studies have shown that ionic zinc (Zn 2*) dissolved in the mouth shortened manifestations of the common cold significantly, by an unknown mechanism. The observed immediate effect on symptoms is consonant with osmotic transport of Zn 2., placing a temporary chemical clamp on critical nerves. It is proposed that transient elevation of Zn 2÷ concentration in and around the nasal cavity facilitates Zn 2÷complexation with known intercellular adhesion molecule binding sites on rhinovirus surfaces which prevents rhinovirus binding to cells and interrupts infection. The crystallographically determined surface of rhinovirus-14 has been found to contain binding sites for at least 360 Zn 2., Such binding of Zn 2÷would be stabilized by numerous histidine, methionine, tyrosine and carboxyl/ carboxylate groups known to line the HRV-14 surface canyons. The resulting blockage of HRV docking with intercellular adhesion molecule binding sites is proposed to be responsible for the observed reduction of the duration of colds by statistically significant and clinically meaningful times.

Introduction In 1984, a double-blind clinical investigation of the effect of zinc gluconate tablets dissolved in the mouth (as opposed to tablets swallowed whole) on the course of the common cold was highly suggestive of the possibility that zinc ion delivered in this way could both shorten the duration of colds and reduce symptom severity by clinically significant amounts (1). If this were indeed the case, then it appeared that a

safe, inexpensive and effective therapeutic agent was in hand, and that its use by the general populace could have a major beneficial effect on public health and the national economy (2). However, this did not prove to be the case for a variety of reasons having little to do with the actual efficacy of ionic zinc for this purpose. First, the delivery of ionic zinc in the mouth was an immediate roadblock because of the unpalatable nature of the clinically tested material, i.e. unflavored zinc gluconate. In fact, the taste had been a serious

Date received 26 July 1995 Date accepted 23 August 1995

295

296

MEDICAL HYPOTHESES

operational problem with the clinical study (1), being responsible in part for a high drop-out rate. This was particularly prevalent in the treatment group, which cast some doubt on the validity of that study. Zinc gluconate was chosen for the study because of its long history as an innocuous dietary supplement, its availability in high purity at a reasonable price, and its status as a GRAS (generally regarded as safe) substance. Various attempts by a number of groups to mask the unpleasant taste with standard, pharmaceutically acceptable flavoring agents either failed to hide the taste, or yielded negative results with the common cold (3-5). The use of citric (3) or tartaric (4) acids, or a mannitol-sorbitol mixture (5) resulted in complexes in which the zinc ion was so tightly bound that virtually no ionic zinc was released in the mouth. The high stability constants of Zn(citrate) and Zn(tartarate), as compared to Zn(gluconate)2 confirm this conclusion (Table 1). In addition, measured percentages of free zinc ion in lozenge-stimulated saliva demonstrate the lack of uncomplexed Zn 2÷ when citric acid or mannitol and sorbitol are present (Table 1). After these failed clinical studies with complex-inactivated zinc, it was suggested (6) that only studies with formulations that would release most of the zinc ions in the mouth could be expected to show results similar to those of the original report (1). In fact, this proved to be the case when a palatable formulation of zinc gluconate with glycine in a hard candy base was employed in a large double-blind clinical study (7). The second problem was the lack of a satisfactory mechanism for the action of zinc ions against the common cold in vivo. Although it has been thoroughly established that ionic zinc has strong activity against rhinovirus in vitro (8,9), there was no apparent mechanism for the in vivo transport of zinc ions from the mouth and throat to the nasal cavity - the presumed site of antiviral activity. Furthermore, the degree and rate of onset of symptomatic relief reported in the original study (1) had no precedent involving the use

Table 1 List of stability constants for a selected group of zinc complexes Complexing agent(s)

PKstab (13)

% Free Zn 2+ (saliva) (13)

Gluconate Gluconate and glycine Citrate Mannitol and sorbitol Tartrate Acetate

1.7 1.6" 4.8 > 4.5* 2.7 1.6

91 93 0 0 62* 94*

* Estimated by direct proportion to the experimental values in this table.

of an inorganic ion. In fact, zinc dissolved in the mouth seemed to have some nasal cleating effect similar to the well-known antihistamines (10) and decongestants (11). During this time, there was only one published clinical study that did show a significant reduction of symptoms by a zinc gluconate lozenge that did not have strong complexing components (12). In the face of these formidable hurdles and the negative clinical studies of the late 1980s, balanced only by the aforementioned positive study, the provocative first study (1) was relegated to curiosity status.

Recent clinical observations Piqued by the apparent efficacy of zinc ions in the first study (1), and armed with the hypothesis that the failure of several subsequent clinical trials (3-5) was due to the non-delivery of ionic zinc in the mouth (6), one of the present authors (JCG) initiated preclinical studies of a new formulation designed to deliver ionic zinc. The combination of zinc gluconate and glycine resulted in a palatable lozenge that releases more than 90% of the zinc ions in the mouth (13). In the same study, it was shown that zinc gluconate lozenges with citric acid or with mannitol and sorbitol do not release Zn 2÷ into saliva when they are dissolved in the mouth (Table 1). This information confirmed the probable reason for the result of the studies that found no effect of zinc on the common cold. It also provided justification for a large-scale clinical trial with the lozenge that does release ionic zinc in the mouth. The clinical trial was carried out in 1990 and reported in 1991 (14) and 1992 (7). The major findings of the double-blind study were (a) a 42% (p < 0.05) reduction in mean cold duration if active treatment was begun less than 2 days after the onset of symptoms, and (b) marked reductions in both numbers and severity of symptoms for those patients receiving active treatment, as compared to placebo. A second placebo-controlled double-blind study confirms this result, with a 50% (p < 0.001) reduction in mean cold duration when active treatment was begun within 24 h of the onset of symptoms. An unanticipated observation, not included in the study plan, was a very common report of unusually rapid reduction of symptom severity among patients on active medication. In fact, very noticeable symptomatic relief was often reported within 1-3 min after insertion of the lozenge in the mouth. It appeared that even if the cold was well-established, symptomatic relief was substantial and was repeated with each use of the lozenge on the approximately 2 h schedule. The observation of a

HOW DOES ZINC MODIFY THE COMMON COLD?

very rapid effect on symptoms was interesting, but was difficult to rationalize as an effect of the antiviral activity of the zinc ion.

Rational mechanisms

L Relief of symptoms The very rapid onset of symptomatic relief is an observable fact to be explored. When it was first noted, its possible reality was rejected as it seemed utterly implausible and contrary to a priori expectation. When the observation was found to be consistently repeatable, the possibility that it was an actual occurrence had to be considered. Due to the uncertain mechanism of action, it was not included as a planned parameter in the protocol of a large clinical study. Subsequent comments from the clinical subjects and investigators were convincing evidence that the rapid relief was a real phenomenon. Calculations of zinc ion concentration and the known interactions of zinc ions with protein, e.g. the ubiquitous zinc fingers (15) that now appear to be important structures in many biological settings, led to fascinating conclusions about a possible mechanism to explain these observations.

Determination of zinc ion concentration. Lozenges used in the clinical study weighed 4.5 g and contained 2 3 m g of Zn 2÷ from 179mg of zinc gluconate trihydrate. A pre-clinical investigation showed that one lozenge caused the production of a mean of 25 ml of saliva, including the dissolved lozenge. The calculated mean concentration of Zn 2÷ in the saliva solution, using the 93% availability of zinc as Zn 2÷determined for this preparation (13), is 13.1 millimolar. Since the mean normal concentration of Zn 2÷ in plasma is 100 ~tg/100 ml (16,17), or 0.0153 millimolar, the ratio of Zn 2÷ in saliva to Zn 2÷ in plasma is approximately 850:1. In addition, the Zn 2÷present in plasma is associated with various proteins, and is thus not all present as free ions. The large concentration of Zn 2+ in the saliva provides a very large osmotic gradient of 250 torr 1, favoring the movement of Zn 2÷ across the semi-permeable mucous membranes of the mouth into the blood and lymph vessels in the immediate vicinity of the mouth. These fluids surround and supply the local tissues, including the tfigeminal and facial nerve endings.

~The relative osmotic pressure of Zn 2+ can be calculated by using P~/P2 = M1RT/M2RT where Pl is the osmotic pressure of Zn 2+ in saliva, P2 is the osmotic pressure of Zn 2+ in blood, M 1 is the concentration of Zn 2÷ in saliva, M2 is the concentration of Zn 2+ in blood and T is 37°C.

297

Physical action of zinc ions. The trigeminal nerve innervates the teeth and gums in both upper and lower jaws, the tongue, the nasal cavity, the supraorbital sinuses and the soft tissue of the nose and upper lip. The facial nerve innervates primarily the tongue, roof of mouth and nares, as well as the submandibular and sublingual glands (18). As Zn 2+ is known to bind very strongly with cysteine and histidine in proteins (15), a high local concentration of Zn 2+ around the protein-rich nerve endings would be expected to result in the binding of zinc with the nerves. What would be the expected physiological consequence of such binding? Zinc is a natural component of the nerves' environment, so what could an excess of Zn 2+do that normal levels do not? A hint at the answer is provided by the common observation that finn finger pressure on the upper lip can inhibit an incipient sneeze, with reversibility of the effect when the finger is removed. Inspection of the trigeminal nerve distribution reveals major branches to the left and right of the center line of the upper lip. Evidently, mechanical pressure on these branches interrupts the normal flow of impulses, of which one effect is the temporary interruption of the sneeze signal. The experience with zinc gluconate/glycine lozenges, in which an effect very similar to that of physical pressure is produced promptly upon starting to dissolve a lozenge in the mouth, suggests that Zn 2+ in much greater than normal concentration can interact with trigeminal and facial nerve endings. This binding of Zn 2+ forms a chemical 'clamp' that has characteristics similar to the physical clamp of finger pressure. Whereas the release of the physical clamp allows an immediate return of normal impulse transmission, the chemical 'clamp' of Zn 2+ appears to last until the binding of Zn 2+ to the nerves is reversed by the homeostatic return of elevated plasma Zn 2+ concentration to normal. The fact that the effect of the lozenges seems to last about 2 h (range 1-3 h) (7), suggests that it takes that long for the bound zinc ions to be released from the nerve tissue. The above argument provides a logical and selfconsistent explanation of observed effects of zinc gluconate/glycine lozenges dissolved in the mouth. It suggests that concentrations of Zn 2÷ in the vicinity of the mouth may indeed be temporarily elevated to greater than two-fold above normal. This would show up in the general circulation as no more than a modest increase in Zn 2+ levels over approximately 2-4 h, because of the dilution factor of the whole circulatory system. The established homeostatic control of Zn z+ levels by the body prevents any long-term elevation of Zn 2+concentration. The postulated temporary high local Zn 2+concentration leads naturally to an explana-

298 tion of the intra-nasal antiviral effect of Zn 2÷as delineated in the next section. II. Antiviral Zn 2÷ action in the nose

Recent reports (19,20) brought to the authors' attention 'intercellular adhesion molecules (e.g. ICAM-1) and their role in the binding of rhinovirus to somatic cells. The principal references in the cited reports provide highly detailed descriptions and pictures of the rhinovirus HRV (21,22), ICAM-1 and the structure of its complex with rhinovirus (HRV) as demonstrated by HRV-14 (22). The strong similarity of 78 HRV coat proteins is exemplified by their common binding to ICAM-1 (23). Interference with the attachment of HRV to ICAM-1 would effectively interrupt the viral infection process by blocking virus entry into the cell. It has been pointed out that a major advantage of intervention at the attachment stage is that the binding domain of the viral attachment protein is likely to be conserved in most viral strains that act by attachment to ICAM-1 (24). ICAM-1 is employed as a receptor by the major group of rhinoviruses (Picomaviruses) which cause up to 50% of common colds (25,26). More than 100 immunologically non-cross-reactive rhinoviruses have been investigated and 90% of them bind to ICAM-1 (27). Therefore, an agent which blocks HRV attachment to ICAM-1 is likely to be generally effective against colds caused by rhinoviruses and the emergence of resistant strains of HRV is unlikely. The capsid of HRV is composed of four proteins named VP1, VP2, VP3 and VP4. HRV is a regular icosahedron with 12 pentagonal units on its surface, each terminating in a slightly raised point at each dodecahedral vertex of the icosahedron. Arranged in a circle about each vertex is a relatively deep groove, referred to as a 'canyon' by the investigators (21). The canyon walls are quite steep, descending 25/~ from the highest point on the viral surface. The canyon floor is about 12 /~ wide, and, as is illustrated in Figure 1, can accommodate zinc ions. The amino termini of the coat proteins that form the canyon are anchored deep in the RNA-containing core of the vires while 35 histidine, 150 carboxyl and 445 hydroxyl residues line the circular canyon. On average, approximately 50% of these carboxyl groups have the potential to exist as carboxylate ions at physiological pH, thus providing an anion-rich and geometrically favorable environment to which Zn 2÷ ions will be strongly attracted. The large number of hydroxyl residues will contribute substantially to stabilization of zinc ion complexes, and coupled with the presence of histidine, cysteine and methionine in the protein structure of the canyon walls and floor, the environ-

MEDICAL HYPOTHESES

ment will be expected to bind very strongly with zinc ions. As noted, HRV 'docks' with ICAM-1 on the surface of somatic cells. The amino terminus of ICAM-1 is at the outer end of the molecule on a narrow, wedgeshaped segment that can reach and bind with side chains on the canyon floor of HRV. This allows the HRV to penetrate the cells and replicate, thereby establishing viral infection. The inability of human antibodies to block infection can be explained as a matter of shape. Human antibodies have amino termini on their surfaces as well, but in such a bulky environment that they are unable to reach down into the canyons of HRV to form a tight complex and block binding to ICAM-1. In contrast, zinc ions are small, positively charged spheres that can easily reach the canyon floor and bind to carboxylate, histidine, methionine and tyrosinate groups. A reasonable hypothesis is that the bound zinc ions collectively act as a competitive inhibitor of ICAM- 1. III. Binding o f zinc ions within the rhinovirus canyons

The relative binding strengths of different complexing agents (ligands) in the canyon walls can be inferred by an examination of the stability constants of a group of zinc complexes (Table 1). The stability constant ( I ~ b ) of an inorganic complex is the equilibrium constant for the formation of the complex from the free ion and ligand(s). As the number of carboxylate groups on the ligand increases, the stability constant increases. With an abundance of carboxylate and hydroxyl groups lining a fairly narrow canyon (ca. 12/~), it is probable that more than one group will chelate Zn 2*. As a resuit, zinc ions can be expected to be strongly attracted to the canyon, and to be bound tightly after arrival. At high concentrations of Zn 2÷, the number of zinc ions bound in the canyons should be elevated and they should remain long after the ambient Zn z÷ concentration has returned to normal physiological levels. The inner canyon walls are composed of viral proteins VP1 and VP3. Although VP2 is present also in the canyon, it is mainly just below the surface of the canyon, so that any binding within the canyon is most likely to occur with locations on VP1 and VP3. Each fifth of the pentagonal canyon is lined with the sidechain carboxylate-containing amino acids, aspartic and glutamic, totalling 21 in VP1 and nine in VP3. There are therefore a total of at least 48 'extra' carboxyls, i.e. not part of an amide group, per fifth of a canyon, or 150/canyon and a grand total of 1800/ virus. Thus, although the 'extra' acidity would be expected to be partially neutralized by the basic amino acids lysine and arginine in VP1 and VP3 (totalling

299

HOW DOES ZINC MODIFY THE COMMON COLD?

Fig. 1 Model of HRV-14 coat protein showing all symmetry elements (green sphere). Three pentagonal canyons are highlighted by zinc ions (small orange spheres) attached to the floors of the canyons. Zinc ions in this model are considerably larger than in reality to facilitate visualization.

26/fifth canyon and 1560/virus) it is clear that each virus possesses at least 1800 potential carboxylate ions and that there are at least 240 other carboxyl groups that are not already neutralized by basic groups already present in the viral coat structure. There are three methionines, at positions 151,221 and 224 of VP1 on the 1/5th slice of the canyon floor, which are situated such that when Zn 2÷binds to them they physically block the binding of ICAM- 1. The proposed binding area of ICAM-1 includes Pro 155, His 220 and Ser 223 of VP1 (28). It can be assumed that these residues mark the general neighborhood of binding of ICAM-1 in the HRV coat protein canyon. The footprint of ICAM-1 is considerably larger than the area bounded by Pro 155, His 220 and Ser 223 of VP1

(22). The binding area on ICAM- 1 carries a net positive charge, thus increasing the affinity of ICAM-1 for the canyon. It can be seen in Figure 2 that the three methionines are close in space to the ICAM-1 binding sites. When the electrostatically negative character of the canyon and the presence in the canyon of strategically placed and powerful transition metal chelating moieties such as methionine, histidine and tyrosine are considered, it becomes apparent why ICAM-1 is attracted to the canyon, and why Zn 2÷ will be attracted there as well. The process envisioned is one in which the zinc ions first interact with and neutralize the negative charge of carboxylates along the canyon walls. Subsequent zinc ions then descend to the canyon floor and bind with VP1 constituents. Thus ICAM-1 binding is

300

MEDICALHYPOTHESES Vial

23

re3

)41

m

nNA ] . W ~

N

I

Fig. 2 Depictionof the geometricconfigurationof HRV-14viral protein VP1. The areas of greatest interest are in the I~E2(residues 155-161) and the ~H (residues 223-230) sheets. Reproducedwith permission fromreference (21). inhibited by both neutralization of negative charges and physical blockage of the canyon. Modeling of the binding of zinc ions to the canyons in HRV started with the crystal structure of HRV-14 complexed with the inhibitor molecule 1-[6-(2-chloro4-methoxyphenoxy)hexyl]imidazole (21). This crystal structure clearly shows the inhibitor molecule nestled in a specific part of the canyon. If zinc ions are thought to block ICAM-1 binding, then it can be reasonably assumed that Zn 2÷ must bind in the same area of the canyon as the inhibitor molecule. The location of the inhibitor molecule was close to that of the proposed binding area of ICAM-1 (Pro 155, His 220, Ser 223 of VP1), thus confirming the chosen portion of the canyon. Visualization of the crystal structure using CAChe software 2 on a Macintosh Ilci was followed by removal of the inhibitor molecule from the picture and consideration of possible Zn 2+binding sites. Only the smallest repeating unit of HRV was used which corresponds to one-fifth of one circular canyon. The inserted zinc ions were assumed to prefer a tetrahedral coordination environment with four ligating atoms, and each coordination environment was completed with water molecules 3. Six sites were found on VPI: Met 151, 221 and 224; Tyr 128 and 152; His 145. After minimization, each Zn 2÷was found to be in an approximately tetrahedral coordination environment with reasonable metal-ligand bond distances. As can be seen in Figure 3, the zinc ions bound to these residues line the canyon floor and block access to the floor by ICAM-1. The zinc ions bound to Met 221, His 245 and Tyr 128 project into the canyon floor. In contrast, the zinc ion bound to Tyr 152 projects upward into the space immediately above the canyon floor. The zinc ion

associated with Met 224 sits in a pocket of the canyon floor and the zinc ion bound to Met 151 projects into the next repeating unit of the canyon floor. Six binding sites for zinc ions in the smallest repeating unit of HRV imply that a minimum of 360 zinc ions can bind to the HRV canyon floors overall. In addition, zinc ions are postulated to bind to carboxylate groups along the canyon walls. The question remains: will there be enough free zinc ions available to bind completely with HRV present in the upper respiratory tract? A rough estimate of the number of virus particles in the upper respiratory tract can be made by considering the number of virus particles shed by people with colds (12,29). Approximately 107-109 virus particles are present, which corresponds to a concentration range o f 10-ts-10-t6 millimolar. As discussed previously, the concentration of free zinc ions achieved in the saliva with the zinc gluconate/glycine lozenges is 13.1 millimolar. Comparison of the relative concentration of zinc ions and HRV reveals a 1012excess of Zn 2+ over HRV particles after consideration of the dilution effects inherent in the movement of Zn 2+from saliva to the upper respiratory tract 4. The loss of zinc through transport out by local circulation is insignificant, as Zn 2+ is being rapidly replaced by osmotic transport from the mouth. The great excess of zinc ions would ensure that Zn 2+would bind to HRV at all possible places and thus block HRV from adhering to ICAM-1 and infecting somatic ceils. If zinc ions indeed operate as postulated, it is logical to speculate on the efficacy of zinc salt solutions introduced by nasal spray or drip. This approach has been tried a number of times, but has not succeeded because of moderate to severe tissue irritation caused by this direct application to nasal tissues. Although the oral route employing the lozenges would seem to

2Personal CAChe,Vs.3.6. CACheScientific, Divisionof Oxford Molecular GroupPLC, Beaverton, OR, 1994. 3Minimization of the Zn2÷positions was achievedusing MM2 (Allinger, 1977#22) and augmentedforcefield parameters, as implemented by CAChe.Onlythe most essential part of the repeating unit of the canyonwas used to minimizecomputation time. As expected, the 3 A resolutioncrystal structure did not have hydrogenatompositions. Therefore,hydrogenatomswere~ddedin the best calculatedpositions to the protein atoms for completeness. All atoms of the protein coat section were lockedinto position, and the zinc ions and watermoleculeswere allowedto movefreely. Bonds betweenZn2÷ions and ligating atoms were assumed to be coordinate covalent in nature. Tetrahedral coordination about zinc ions was assured by locking ligating atom angles. 4 A conservative estimate of the local increase in zinc ion concentrationin bloodand lymphdue to osmotic transfer from the

buccal cavityis 1% of 13.1 millimolaror 0A31 millimolar. Using the averagenumberof 10s HRV virions/Lat the site of infection,the excess of Zn2~overvirionsis calculatedto be (1,31 x 10"4M Zn2*)/ (10s virions*L-l/6.02× 1023virions*mo1-1)= g × 10HZn~/virion.

301

HOW DOES ZINC MODIFY THE COMMON COLD?

Fig. 3 Stereoscopic representation of the binding of Zn 2" on the VP1 canyon floor at Met 151, 211 and 224, at Tyr 128 and 152, and at His 245. The view is looking down the canyon floor, and is rotated about 900 counterclockwise from the view in Figure 2. Zinc binding at these sites would effectively block ICAM-I binding to Pro 155, His 220 and Ser 223 by direct steric interference (Met 151-Zn with Pro 155. Tyr 152-Zn with Pro 155, Met 221-Zn and Met 224-Zn with Ser 223 and His 220). The other sites, His 245-Zn and Tyr 128-Zn, would cause general structural perturbation in the ICAM-I binding neighborhood. Color legend: C-black, N-blue, O(protein)-red, O(water)-pink. S-yellow. Zn-green.

be less direct, it now appears to be fraught with fewer unwanted side effects. According to Moffat (20), some major pharmaceutical houses have mounted large research efforts to discover or synthesize small molecules that will mimic ICAM-1, bind tightly to HRV and block its binding to cells, These efforts are admitted to be at least years away from achieving practical results. Based on published studies (1,7), zinc ions appear to be ideal agents to block HRV infection. The present hypothesis suggests a viable mechanism that presents a large concentration of Zn 2÷ in the vicinity of freshly arrived HRV in the nose, where zinc ions bind tightly with HRV and block its ability to infect cells. In addition,

it appears that this can actually be done by simply elevating the local concentration of Zn 2+, an essential ion for which homeostatic controls already exist.

Conclusion The demonstrated efficacy against the common cold of lozenges which deliver a high percentage of zinc ions to the mouth and nasal cavity has led to a proposed mechanism of action. The high local concentration of zinc ions in a solution formed by dissolving a zinc gluconate/glycine lozenge in saliva is thought to lead to two distinct effects. Following the osmotic transport

302 of zinc ions across the buccal membranes, the binding of zinc ions to trigeminal and facial nerve endings is proposed to create a fast-acting chemical 'clamp' that suppresses nerve impulses, thereby inhibiting sneezing, nasal discharge and nasal congestion. This accounts for the unusually rapid relief of symptoms when ionic zinc is dissolved in the mouth. It also supports the osmotic transport of zinc ions to produce temporary local Zn 2÷concentrations in blood and lymph that are at least an order of magnitude higher than normal. Secondly, it is proposed that the binding of zinc ions to residues in the canyons of the HRV protein coat result in the competitive inhibition of HRV binding to somatic cells through ICAM-1. It appears that the long soughtafter 'cure' of the common cold is in hand as an inexpensive and safe product. Zinc gluconate/glycine lozenge therapy can both relieve the acute symptoms of the common cold and give the immune system a helping hand by temporarily blocking HRV infection of cells, thus shortening the average duration of the cold.

Acknowledgements The authors wish to acknowledge Herman Zinnen at CAChe Scientific for constructing the CAChe file of HRV-14 with the inhibitor molecule 1-[6-(2-chloro-4-methoxyphenoxy) hexyl]imidazole from the crystallographic information available through Internet (PDB file PDB 1HRI.ENT), and Robert L. Pollack, PhD, Professor Emeritus, Temple University School of Medicine and Dentistry, for expert assistance in production of computer simulations and pictures. Grant support for the purchase of the CAChe program came from a Hofstra University Presidential Award and a Hofstra University Faculty Research and Development grant.

MEDICAL HYPOTHESES

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