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EFdA (4’-C-ethynly-2-fluoro-2’-deoxyadenosine)
prevents the emergence of resistant HIV mutants and is over 400 times more
active than AZT and several orders of magnitude more active than the clinical
creverse-transcriptase (RT) inhibitory 2’, 3’-dideoxy nucleoside drugs, very
low toxic, very long acting, and very useful for prophylaxis.
EFdA is
now under clinical investigation by Merck & Co. as MK-8591. In the
beginning of my talk, a general idea for the development of anti-viral modified
nucleosides based on the mutation of viruses will be presented. Next, the
development of EFdA is discussed and then the current results of the clinical
trials of EFdA reporeted by Merck & CO. will be presented. For the design
of the modified nucleoside that could solve the critical problems of the
clinical drugs (1) Emergence of drug-resistant HIV mutants, (2) Adverse effects
by drugs, (3) Necessity to take considerable amount of drugs (4) four working
hypotheses were proposed. They are (1) The way to prevent the emergence of drug-resistant
HIV mutants, (2) the way to decrease the toxicity of modified nucleosides, (3) the
way to provide the modified nucleoside with the stability to both enzymatic and
acidic cleavage of glycosyl linkage for long acting in the body, and (4) the
differenct substrate selectivity between RT and human DNA polymerases could
enable to develop anti-HIV modified nucleoside that is selectively active to
HIV and very low toxic to human beings. 4’-C-Substituded-2’-deoxynucleoside
(4’SdN) which has 3’-OH was designed as the nucleoside that could satisfy these
hypotheses. The study on 4’SdN has successfully resulted in the development of
EFdA [modified at the two positions (2 and 4’) of the physiologic 2’-deoxyadenosine]
with very excellent anti-HIV activity.
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