Kodama E, Ohrui H, Gatanaga H, Shigeta S, Matsuoka M, Mitsuya H; Conference on Retroviruses and Opportunistic Infections.

Program Abstr 8th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 8th 2001 Chic Ill. 2001 Feb 4-8; 8: 134 (abstract no. 305).

Inst for Virus Res, Kyoto Univ, 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 IC50 values ranging from 0.4 to 10 nanomolar. 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(Y181C) and 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.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Anti-HIV Agents
• Drug Resistance
• HIV Infections
• HIV Seropositivity
• HIV-1
• HIV-2
• In Vitro
• Nucleosides
• Pharmaceutical Preparations
• Reverse Transcriptase Inhibitors
• Zidovudine
• antagonists & inhibitors
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• GWAIDS0006592

UI: 102244088

From Meeting Abstracts