305   4´-Ethynyl Nucleoside Analogs: Potent Inhibitors Active against Multi-Drug-Resistant HIV Variants In Vitro.

E. Kodama*¹, H. Ohrui², H. Gatanaga³, S. Shigeta⁴, M. Matsuoka¹, and H. Mitsuya⁵.
¹Inst. for Virus Res., Kyoto Univ., Japan;²Tohoku Univ., Sendai, Japan;³NCI, NIH, Bethesda, .MD;⁴Fukushima Med. Univ. Sch. of Med., Japan; and⁵Kumamoto Univ. Sch. of Med., Japan.

Background and Methods:A series of 4´-substituted nucleosides were designed, synthesized, and identified to be active against a wide spectrum of HIV, including a variety of laboratory strains of HIV-1 and -2 and primary clinical HIV-1 isolates.

Results:Among 4´-substituted nucleosides examined, 4´- E -2´-deoxycytidine (4´- E -dC), 4´- E -2´- deoxyadenosine (4'- E -dA) and 4´- E -2´-deoxyribosyl diaminopurine (4´- E -dDAP) were potent inhibitors and suppressed the replication of various drug-resistant HIV-1 clones, including HIV-1_M41L/T215Y, HIV-1_L74V, HIV- 1_K65R, HIV-1_{M41L/T69S-S-G/T215Y}, and HIV-1_{A62V/V75I/F77L/F116Y/Q151M}, with IC₅₀values ranging from 0.4 to 10 nM. Moreover, these analogs inhibited the replication of multi-drug-resistant clinical strains carrying a variety of drug-resistance-related amino acid substitutions isolated from HIV-1-infected individuals who had failed over 10 different anti-HIV agents. 4´- E analogs also inhibited non-nucleoside RT inhibitor-resistant HIV-1_Y181Cand 2 strains of HIV-2 and showed an anti-HIV-1 profile comparable to that of zidovudine in drug addition experiments. Anti-HIV-1 activity of 4´- E -dC was reversed by the addition of 2´-deoxycytidine, while that of 4´- E -dA was not reversed by 2´-deoxyadenosine, strongly suggesting that 4´- E nucleosides suppress HIV replication by acting as nucleoside reverse transcriptase inhibitors. 4´- E -dC, 4´- E -dA, and 4´- E -dDAP were all found to be acid resistant.

Conclusions:Further development of 4´- E nucleosides, in particular 4´- E -dC, 4´- E -dA and 4´- E -dDAP, as potential therapeutics for infection with multi-drug-resistant HIV-1 is warranted.