当前位置： SCI文献检索 > JOURNAL OF VIROLOGY期刊下所有文献 > Altered substrate specificity of drug-resistant human immunodeficiency virus type 1 protease.

Altered substrate specificity of drug-resistant human immunodeficiency virus type 1 protease.

Abstract：

:Resistance to human immunodeficiency virus type 1 protease (HIV PR) inhibitors results primarily from the selection of multiple mutations in the protease region. Because many of these mutations are selected for the ability to decrease inhibitor binding in the active site, they also affect substrate binding and potentially substrate specificity. This work investigates the substrate specificity of a panel of clinically derived protease inhibitor-resistant HIV PR variants. To compare protease specificity, we have used positional-scanning, synthetic combinatorial peptide libraries as well as a select number of individual substrates. The subsite preferences of wild-type HIV PR determined by using the substrate libraries are consistent with prior reports, validating the use of these libraries to compare specificity among a panel of HIV PR variants. Five out of seven protease variants demonstrated subtle differences in specificity that may have significant impacts on their abilities to function in viral maturation. Of these, four variants demonstrated up to fourfold changes in the preference for valine relative to alanine at position P2 when tested on individual peptide substrates. This change correlated with a common mutation in the viral NC/p1 cleavage site. These mutations may represent a mechanism by which severely compromised, drug-resistant viral strains can increase fitness levels. Understanding the altered substrate specificity of drug-resistant HIV PR should be valuable in the design of future generations of protease inhibitors as well as in elucidating the molecular basis of regulation of proteolysis in HIV.

journal_name

J Virol

journal_title

Journal of virology

authors

Dauber DS,Ziermann R,Parkin N,Maly DJ,Mahrus S,Harris JL,Ellman JA,Petropoulos C,Craik CS

doi

10.1128/jvi.76.3.1359-1368.2002

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

1359-68

issue

3

eissn

0022-538X

issn

1098-5514

journal_volume

76

pub_type

杂志文章

相关文献

JOURNAL OF VIROLOGY文献大全