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Aspartic proteinases in disease: A structural perspective

Cooper, J.B. (2002) Aspartic proteinases in disease: A structural perspective Current Drug Targets, 3, (2), pp. 155-173.

Record type: Article

Abstract

The aspartic proteinases are a family of enzymes involved in a number of important biological processes. In animals the enzyme renin has a hypertensive action through its role in the renin-angiotensin system. The retroviral aspartic proteinases, such as the HIV proteinase, are essential for maturation of the virus particle and inhibitors have a proven therapeutic record in the treatment of AIDS. The lysosomal aspartic proteinase cathepsin D has been implicated in tumorigenesis and the stomach enzyme pepsin, which plays a major physiological role in hydrolysis of acid-denatured proteins, is responsible for much of the tissue damage in peptic ulcer disease. Since aspartic proteinases also play major roles in amyloid disease, malaria and common fungal infections such as candidiasis, inhibitors to these enzymes are much sought after as potential therapeutic agents. In all aspartic proteinases, the catalytic aspartate residues are involved in an intricate arrangement of hydrogen bonds involving a solvent molecule which is presumed to be water. The catalytic mechanism is thought to involve nucleophilic attack of the active site water molecule on the scissile bond carbonyl generating a tetrahedral gem-diol intermediate. The design of inhibitors generally involves the use of short oligopeptides containing a transition state analogue which mimic this tetrahedral intermediate. The application of structure-based drug design to members of the aspartic proteinase family is the main subject of this review.

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More information

Published date: 1 April 2002
Keywords: aspartic proteinasases, aids, amyloid disease, candidiasis, candida albicans, peptic ulcer disease, malaria, aspartic proteinase inhibitors, norstatine

Identifiers

Local EPrints ID: 56272
URI: http://eprints.soton.ac.uk/id/eprint/56272
ISSN: 1389-4501
PURE UUID: ae20e055-04a9-4c44-a8e0-dfbbb621855e

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Date deposited: 08 Aug 2008
Last modified: 17 Jul 2017 14:31

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Contributors

Author: J.B. Cooper

University divisions

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