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Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.

Abstract：

:By using a structure-based computer-assisted search, we have found a butyrophenone derivative that is a selective inhibitor of the human immunodeficiency virus 1 (HIV-1) protease. The computer program creates a negative image of the active site cavity using the crystal structure of the HIV-1 protease. This image was compared for steric complementarity with 10,000 molecules of the Cambridge Crystallographic Database. One of the most interesting candidates identified was bromperidol. Haloperidol, a closely related compound and known antipsychotic agent, was chosen for testing. Haloperidol inhibits the HIV-1 and HIV-2 proteases in a concentration-dependent fashion with a Ki of approximately 100 microM. It is highly selective, having little inhibitory effect on pepsin activity and no effect on renin at concentrations as high as 5 mM. The hydroxy derivative of haloperidol has a similar effect on HIV-1 protease but a lower potency against the HIV-2 enzyme. Both haloperidol and its hydroxy derivative showed activity against maturation of viral polypeptides in a cell assay system. Although this discovery holds promise for the generation of nonpeptide protease inhibitors, we caution that the serum concentrations of haloperidol in normal use as an antipsychotic agent are less than 10 ng/ml (0.03 microM). Thus, concentrations required to inhibit the HIV-1 protease are greater than 1000 times higher than the concentrations normally used. Haloperidol is highly toxic at elevated doses and can be life-threatening. Haloperidol is not useful as a treatment for AIDS but may be a useful lead compound for the development of an antiviral pharmaceutical.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

DesJarlais RL,Seibel GL,Kuntz ID,Furth PS,Alvarez JC,Ortiz de Montellano PR,DeCamp DL,Babé LM,Craik CS

doi

10.1073/pnas.87.17.6644

subject

Has Abstract

pub_date

1990-09-01 00:00:00

pages

6644-8

issue

eissn

0027-8424

issn

1091-6490

journal_volume

pub_type

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Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.