期刊论文详细信息
TETRAHEDRON 卷:74
Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146
Article
Agbowuro, Ayodeji A.1  Mazraani, Rami2  McCaughey, Laura C.3,4  Huston, Wilhelmina M.2  Gamble, Allan B.1  Tyndall, Joel D. A.1 
[1] Univ Otago, Sch Pharm, Dunedin 9054, New Zealand
[2] Univ Technol Sydney, Sch Life Sci, 15 Broadway, Ultimo, NSW 2007, Australia
[3] Univ Technol Sydney, iThree Inst, 15 Broadway, Ultimo, NSW 2007, Australia
[4] Univ Oxford, Dept Biochem, South Pk Rd, Oxford OX1 3QU, England
关键词: Chlamydia;    HtrA inhibition;    Protease;    JO146;    Diastereomers;   
DOI  :  10.1016/j.tet.2017.10.031
来源: Elsevier
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【 摘 要 】

JO146, a mixture of two diastereomers of a peptidic phosphonate inhibitor for Chlamydial HtrA (CtHtrA), has reported activity against Chlamydia species in both human and koala. In this study we isolated the individual diastereomers JO146-D1 and JO146-D2 (in >= 90% purity) and assessed their individual inhibitory activity against the serine protease human neutrophil elastase (HNE) which is structurally and functionally related to CtHtrA, as well as in Chlamydia trachomatis cell culture. JO146-D2 [S,S,R-Boc-Val-Pro-Val(P)(OPh)(2)], the isomer with the physiologically relevant valine at P1, had an approximate 2.5 - fold increase in in vitro HNE inhibition potency over JO146-D1 [S,S,S-Boc-Val-Pro-Val(P)(OPh)(2)] and greater than 100 fold increase in cellular anti-chlamydial activity compared to JO146-D1 which possesses the unnatural valine at P1. JO146 and the individual diastereomers had excellent selectivity for the serine protease HNE over the potential off-target serine proteases trypsin and chymotrypsin. Docking studies supported the biological data with a geometrically unfavoured interaction observed between the P1 valine residue of JO146-D1 and the enzyme S1 sub-pocket. (C) 2017 Elsevier Ltd. All rights reserved.

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