AEGiS-11IAC: Identification of protease inhibitors containing allophenylnorstatine active against both wild-type and KNI-272-resistant HIV-1 variants.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Identification of protease inhibitors containing allophenylnorstatine active against both wild-type and KNI-272-resistant HIV-1 variants.

Int Conf AIDS 1996 Jul 7-12; 11:220 (abstract no. Tu.A.260)
Tanaka M, Mimoto T, Anderson B, Gulnik S, Bhat TN, Yusa K, Hayashi H, Kiso Y, Erickson JW, Mitsuya H; The Experimental Retrovirology Section, Medicine Branch, National Cancer Institute, Bethesda, MD, USA. Fax: 301-402-0709.

OBJECTIVE: HIV-1 develops in vitro a high degree of resistance to KNI-272, a substrate-based, peptide-mimetic HIV protease inhibitor containing allophenylnorstatine (Apns), by acquiring mutations in the protease-encoding gene. We synthesized various Apns-containing protease inhibitors and identified several compounds showing activity against both wild-type and KNI-272-resistant HIV-1.

METHODS: Forty-four Apns-containing inhibitors were tested against HIV-1LAI, KNI-272-resistant HIV-1 (HIV-1272R, and various infectious HIV-1 clones containing subsets of mutations conferring KNI-272-resistance. The IC50 values of KNI-272 against HIV-1LAI and HIV-1272R were 0.04 micromolar and 2 micromolar, respectively.

RESULTS: Of 44 Apns-containing inhibitors, KNI-241 and its related compounds showed activity against both HIV-1LAI and HIV-1272R in vitro. Among the inhibitors which proved to be active against HIV-1HXB2D and KNI-272-resistant infectious HIV-1 clones, KNI-241 was most potent (see table). Inhibition constants (Ki) determined using recombinant mutant proteases corroborated the differential activity of these inhibitors against HIV-1HXB2D and KNI-272-resistant clones. X-ray crystallographic analysis and modeling studies of enzyme-inhibitor complexes were also performed. (table: see text)

CONCLUSIONS: We identified several Apns-containing protease inhibitors which are active against both wild-type HIV-1 and variants resistant to KNI-272. Using these inhibitors as lead compounds and X-ray crystallography data of enzyme-inhibitor complexes, the design of new types of protease inhibitors, which tightly bind with the wild-type and mutant enzymes and delay or block the development of certain protease inhibitor-resistant HIV-1 variants, may become possible.

Keywords: AEGIS, HIV-1, Phenylbutyrates, HIV Protease Inhibitors, Oligopeptides, HIV Protease, HIV, Anti-HIV Agents, Reverse Transcriptase Inhibitors, Mutation, Inhibitory Concentration 50, 3-amino-2-hydroxy-4-phenylbutanoic acid, kynostatin 272, In Vitro, genetics, ICA11

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TuA260