Creation of low toxic reverse-transcriptase inhibitory nucleosides that prevent the emergence of drug-resistant HIV variants

Although the Highly Active Anti-Retroviral Therapy (HAART) has dramatically improved the quality of life and the prognosis of patients infected with HIV, development of more active and less toxic drugs that prevent the emergence of drug-resistant HIV variants is strongly required, due to the emergence of new drug-resistant HIV variants, need of taking a large quantity of drugs, and side effects of the drugs. The principal author has proposed a concept to prevent the emergence of the HIV variants resistant to reverse-transcriptase (RT) inhibitory nucleosides. Based on the concept, 4′ -C-substituted-2′-deoxynucleoside (4′Sd-N)* ¹ was designed as the anti-HIV nucleoside that could prevent the emergence of resistant HIV variants. Various kinds of 4′Sd-N were synthesized and evaluated for biological activity. 2′-Deoxy-4′-C-ethynyl-2-fluoroadenosine (4′Ed-2FA) which is stable to adenosine deaminase turned out to be highly active against all HIV-1 including multi-drug resistant variants and very lowly toxic, and so far no HIV-1 variants resistant to it emerged. These results suggest that once-daily-dosing schedule of 4′Ed-2FA is possible presumably with few side effects and warrant that 4′Ed-2FA be further developed as a potential therapeutic for HIV-1 infection.