In vitro inhibition of HIV‐1 proteinase by cerulenin

FEBS Letters

Knoop, Marie-Therés²  Nicolaou, George³  Jupp, Raymond¹  Moelling, Karin²  Schulze, Thomas²  Pearl, Laurence H.³  Kay, John¹ 

[1] Department of Biochemistry, University College of Wales, PO Box 903, Cardiff CF1 1ST, UK;Max-Planck Institut für Molekular Genetik, Ihnestrasse 73, D-1000 Berlin 33, FRG;Department of Biochemistry, University College London, Gower Street, London WC1E 6BT, UK

关键词: Retroviral proteinase inhibitor;    Human immunodeficiency virus;    Catalytic mechanism;   

DOI  :  10.1016/0014-5793(90)80595-A

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Retroviruses encode proteinases necessary for the proteolytic processing of the viral gag and gag-pol precursor proteins. These enzymes have been shown to be structurally and functionally related to aspartyl proteinases such as pepsin and renin. Cerulenin is a naturally occurring antibiotic, commonly used as an inhibitor of fatty acid synthesis. Cerulenin has been observed to inhibit production of Rous sarcoma virus and murine leukaemia virus by infected cells, possibly by interfering with proteolytic processing of viral precursor proteins. We show here that cerulenin inhibits the action of the HIV-1 proteinase in vitro, using 3 substrates: a synthetic heptapeptide (SQNYPIV) which corresponds to the sequence at the HIV-1 gag junction, a bacterially expressed gag precursor, and purified 66 kDa reverse transcriptase. Inhibition of cleavage by HIV-1 proteinase required preincubation with cerulenin. Cerulenin also inactivates endothiapepsin, a well-characterised fungal aspartyl proteinase, suggesting that the action of cerulenin is a function of the common active site structure of the retroviral and aspartic proteinases. Molecular modelling suggests that cerulenin possesses several of the necessary structural features of an inhibitor of aspartyl proteinases and retroviral proteinases. Although cerulenin itself is cytotoxic and inappropriate for clinical use, it may provide leads for the rational design of inhibitors of the HIV proteinase which could have application in the chemotherapy of AIDS.

【 授权许可】

Unknown