Control and Prevention of HIV/AIDS, STDs & STIs

4’-C-Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA) is attracting much attention due to  its extremely excellent anti-HIV activity and  physiological properties.  EFdA  prevents the emergence of resistant HIV mutants,  is over 400 times more active than AZT and several orders of magnitude more active than  the other clinical reverse-transcriptase inhibitor y 2’, 3’-dideoxynucleoside drugs, very low toxic, very long acting,  and very useful for prophylaxis. EFdA is now under clinical trialsby Merck &  Co. as MK-8591. In the beginning,  a general  idea for the development of anti-viral modified nucleosides is presented, and  next,  the development of  EFdA is discussed and then  the current results of the clinical trials reported by Merck will be presented.  For the design of the modified nucleoside which could solve the critical problems that  the clinical drugs have (emergence of drug-resistant HIV mutants,  adverse effect by drugs, necessity to take  consirerble amount of drugs), 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 stability to both enzymatic and acidic glycolysis for long acting, and (4) it is possible to develop selectively active to HIV and very low toxic to human based on the difference of the substrate selectivity between HIV and human nucleic acid polymerses (cf; the general idea). 4’-C-substituted-2’-deoxy nucleoside (4’SdN) was designed based on the hypotheses (1 and 3), and the additional  modification of 4’SdN was performed  based on the hypothesis (2). The details of the all  hypotheses will be discussed. To prevent the deamination of adenine by adenosine deaminase, a fluorine atom was introduced at the 2-position of adenine. Finally, EFdA, modified at the two position (2 and 4’) of the physiologic 2’-deoxyadenosine and has  extremely excellent anti-HIV activity,  was  successfully developed.