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Metabolic changes associated with the life cycle of African trypanosomes and their relationship to kinetoplast DNA
244
TRYPANOSOMIASIS SEMINAR
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In contrast to the results reported by STUART(1970) DNA from dyskinetoplastic strains of T. brucei, obtained by acriflavine treatment, was found to lack the fast banding satellite DNA. REFERENCES
RIOU, G. & DELAIN, E. (1969). Proc. r,atn. Acad. Sci., U.S.A., 62, 210. SCHILImRAUT,C. A., MaRMUR, J. & DOTY, P. (1962). ft. molec. Biol., 4, 439. STUART, K. (1970) Trans. R. Soc. trop. Med. Hyg., 64, 178.
Further studies on the interaction o f Berenil ( D i m i n a z e n e ) and related c o m p o u n d s with DNA
B. A. NEWTON M.R.C. Biochemical Parasitology Unit, The Molteno Institute, University of Cambridge Berenil has a high affinity for nucleic acid. The drug is rapidly bound by trypanosomes and can readily be detected by ultra-violet microscopy first in the kinetoplast and later in the nucleus. Low concentrations of drug give rise to dyskinetoplastic organisms and direct evidence has been obtained for the selective inhibition ofkinetoplast DNA synthesis (NEwtON and LE PAGE, 1968). Many synthetic drugs and antibiotics are now known to interact with DNA but the majority of these are too generally toxic to be of any practical value as chemotherapeutic agents; this, however, is not so for trypanocides such as Berenil or the phenanthridine drugs. These compounds show specificity of action at two levels: they are selective for certain protozoan parasites within their host and they may also selectively inhibit the synthesis of extranuclear DNA in the kinetoplast of trypanosomes or in mitochondria of other organisms. At present we do not understand the molecular basis of either of these selective activities. In an attempt to learn something about the portions of the Berenil molecule which are responsible for the drug's selective activity eight derivatives of the parent compound have been studed. All have been found to have a high affinity for nucleic acid and to form complexes with DNA, but the growth inhibitory activity of these compounds on the test organism, Trypanosoma mega, varies by two orders of magnitude. Differences in the ability of these compounds to bind selectively to extranuclear DNA have been found and evidence for the formation of different types of DNA/drug complexes has been obtained. The results indicate that free amidino groups are important for cell penetration and provide evidence that the spacing between charged groups in the Berenil molecule is important for the selective binding to DNA. REFERENCE
NEWTON, B. A. & LE PAGE, R. W. F. (1968). Trans. R. Soc. trop. Med. Hyg., 62, 131.
Metabolic changes associated with the life cycle o f African t r y p a n o s o m e s and their relationship to kinetoplast D N A
G. A. M. CROSS A4.R.C. Biochemical Parasitology Unit, The Molteno Institute, University of Cambridge Kinetoplast DNA (kDNA) has been implicated in mitochondrial function by virtue of its cellular location, and because of the observation that naturally occurring and drug
TRYPANOSOMIASIS SEMINAR
.
In contrast to the results reported by STUART(1970) DNA from dyskinetoplastic strains of T. brucei, obtained by acriflavine treatment, was found to lack the fast banding satellite DNA. REFERENCES
RIOU, G. & DELAIN, E. (1969). Proc. r,atn. Acad. Sci., U.S.A., 62, 210. SCHILImRAUT,C. A., MaRMUR, J. & DOTY, P. (1962). ft. molec. Biol., 4, 439. STUART, K. (1970) Trans. R. Soc. trop. Med. Hyg., 64, 178.
Further studies on the interaction o f Berenil ( D i m i n a z e n e ) and related c o m p o u n d s with DNA
B. A. NEWTON M.R.C. Biochemical Parasitology Unit, The Molteno Institute, University of Cambridge Berenil has a high affinity for nucleic acid. The drug is rapidly bound by trypanosomes and can readily be detected by ultra-violet microscopy first in the kinetoplast and later in the nucleus. Low concentrations of drug give rise to dyskinetoplastic organisms and direct evidence has been obtained for the selective inhibition ofkinetoplast DNA synthesis (NEwtON and LE PAGE, 1968). Many synthetic drugs and antibiotics are now known to interact with DNA but the majority of these are too generally toxic to be of any practical value as chemotherapeutic agents; this, however, is not so for trypanocides such as Berenil or the phenanthridine drugs. These compounds show specificity of action at two levels: they are selective for certain protozoan parasites within their host and they may also selectively inhibit the synthesis of extranuclear DNA in the kinetoplast of trypanosomes or in mitochondria of other organisms. At present we do not understand the molecular basis of either of these selective activities. In an attempt to learn something about the portions of the Berenil molecule which are responsible for the drug's selective activity eight derivatives of the parent compound have been studed. All have been found to have a high affinity for nucleic acid and to form complexes with DNA, but the growth inhibitory activity of these compounds on the test organism, Trypanosoma mega, varies by two orders of magnitude. Differences in the ability of these compounds to bind selectively to extranuclear DNA have been found and evidence for the formation of different types of DNA/drug complexes has been obtained. The results indicate that free amidino groups are important for cell penetration and provide evidence that the spacing between charged groups in the Berenil molecule is important for the selective binding to DNA. REFERENCE
NEWTON, B. A. & LE PAGE, R. W. F. (1968). Trans. R. Soc. trop. Med. Hyg., 62, 131.
Metabolic changes associated with the life cycle o f African t r y p a n o s o m e s and their relationship to kinetoplast D N A
G. A. M. CROSS A4.R.C. Biochemical Parasitology Unit, The Molteno Institute, University of Cambridge Kinetoplast DNA (kDNA) has been implicated in mitochondrial function by virtue of its cellular location, and because of the observation that naturally occurring and drug