title: 4'-Ethynyl nucleoside analogs: potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro.
abstract: A series of 4'-ethynyl (4'-E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4'-E-2'-deoxycytidine (4'-E-dC), 4'-E-2'-deoxyadenosine (4'-E-dA), 4'-E-2'-deoxyribofuranosyl-2,6-diaminopurine, and 4'-E-2'-deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 microM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4'-E analogs also suppressed replication of various drug-resistant HIV-1 clones, including HIV-1(M41L/T215Y), HIV-1(K65R), HIV-1(L74V), HIV-1(M41L/T69S-S-G/T215Y), and HIV-1(A62V/V75I/F77L/F116Y/Q151M). Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4'-E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1(Y181C), and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4'-E-thymidine and 4'-E-dC was blocked by the addition of thymidine and 2'-deoxycytidine, respectively, while that of 4'-E-dA was not affected by 2'-deoxyadenosine, similar to the antiviral activity reversion feature of 2',3'-dideoxynucleosides, strongly suggesting that 4'-E analogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4'-E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.
authors: Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors: E I
authors: EI
authors: Kodama
authors: S
authors: S
authors: Kohgo
authors: K
authors: K
authors: Kitano
authors: H
authors: H
authors: Machida
authors: H
authors: H
authors: Gatanaga
authors: S
authors: S
authors: Shigeta
authors: M
authors: M
authors: Matsuoka
authors: H
authors: H
authors: Ohrui
authors: H
authors: H
authors: Mitsuya
mesh_terms: D019380:Anti-HIV Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003853:Deoxyribonucleosides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000502:physiology; D004355:Drug Stability; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests
chemical_list: D019380:Anti-HIV Agents; D003853:Deoxyribonucleosides