Pentapeptide boronic acid inhibitors of Mycobacterium tuberculosis MycP1 protease.
Bioorg Med Chem Lett
; 24(15): 3546-8, 2014 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-24915878
ABSTRACT
Mycosin protease-1 (MycP1) cleaves ESX secretion-associated protein B (EspB) that is a virulence factor of Mycobacterium tuberculosis, and accommodates an octapeptide, AVKAASLG, as a short peptide substrate. Because peptidoboronic acids are known inhibitors of serine proteases, the synthesis and binding of a boronic acid analog of the pentapeptide cleavage product, AVKAA, was studied using MycP1 variants from Mycobacterium thermoresistible (MycP1mth), Mycobacterium smegmatis (MycP1msm) and M. tuberculosis (MycP1mtu). We synthesized the boropentapeptide, HAlaValLysAlaAlaB(OH)2 (1) and the analogous pinanediol PD-protected HAlaValLysAlaAlaBO2(PD) (2) using an Fmoc/Boc peptide strategy. The pinanediol boropentapeptide 2 displayed IC50 values 121.6±25.3 µM for MycP1mth, 93.2±37.3 µM for MycP1msm and 37.9±5.2 µM for MycP1mtu. Such relatively strong binding creates a chance for crystalizing the complex with 2 and finding the structure of the unknown MycP1 catalytic site that would potentially facilitate the development of new anti-tuberculosis drugs.
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MEDLINE
Assunto principal:
Oligopeptídeos
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Inibidores de Proteases
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Proteínas de Bactérias
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Ácidos Borônicos
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Subtilisinas
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article