Virology & Mycology
Open Access
ISSN: 2161-0517
+44 1223 790975
ISSN: 2161-0517
+44 1223 790975
Hiroshi Ohrui
Yokohama University of Pharmacy, Japan
Keynote: Virol Mycol
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 trials by 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 viral and human nucleic acid polymerses. 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 positions (2 and 4��?) of the physiologic 2��?-deoxyadenosine and has extremely excellent anti-HIV activity, was successfully developed.
Hiroshi Ohrui has received his PhD degree (1971) from The University of Tokyo. He has joined Riken in 1966, moved to Tohoku University in 1981 and to Yokohama University of Pharmacy in 2006. He has received several awards including The Japan Society for Analytical Chemistry Award (2004) and Japan Academy Prize (2010). His research interests cover organic synthesis, chemical biology and chiral discrimination.
Email:h.ohrui@hamayaku.ac.jp