Pentapeptide boronic acid inhibitors of Mycobacterium tuberculosis MycP1 protease

Mykhaylo S. Frasinyuk; Stefan Kwiatkowski; Jonathan M. Wagner; Timothy J. Evans; Robert W. Reed; Konstantin V. Korotkov; David S. Watt

doi:10.1016/j.bmcl.2014.05.056

Pentapeptide boronic acid inhibitors of Mycobacterium tuberculosis MycP₁ protease

Mykhaylo S. Frasinyuk, Stefan Kwiatkowski, Jonathan M. Wagner, Timothy J. Evans, Robert W. Reed, Konstantin V. Korotkov, David S. Watt

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 (MycP_1mth), Mycobacterium smegmatis (MycP_1msm) and M. tuberculosis (MycP_1mtu). 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 MycP_1mth, 93.2 ± 37.3 μM for MycP _1msm and 37.9 ± 5.2 μM for MycP_1mtu. 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.

Original language	English
Pages (from-to)	3546-3548
Number of pages	3
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2014.05.056
State	Published - Aug 1 2014

Bibliographical note

Funding Information:
D.S.W. was supported by the Office of the Dean of the College of Medicine and by NIH Grant Number P20 RR020171 from the National Institute of General Medical Sciences to L. Hersh, PI. K.V.K. was supported by the NIH/NIGMS Grant P20GM103486 . The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

Keywords

Boronic acid
Inhibitor
Pentapeptide
Protease

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2014.05.056

Cite this

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title = "Pentapeptide boronic acid inhibitors of Mycobacterium tuberculosis MycP1 protease",

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 MycP 1msm 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.",

keywords = "Boronic acid, Inhibitor, Pentapeptide, Protease",

author = "Frasinyuk, {Mykhaylo S.} and Stefan Kwiatkowski and Wagner, {Jonathan M.} and Evans, {Timothy J.} and Reed, {Robert W.} and Korotkov, {Konstantin V.} and Watt, {David S.}",

note = "Funding Information: D.S.W. was supported by the Office of the Dean of the College of Medicine and by NIH Grant Number P20 RR020171 from the National Institute of General Medical Sciences to L. Hersh, PI. K.V.K. was supported by the NIH/NIGMS Grant P20GM103486 . The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS. ",

year = "2014",

month = aug,

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doi = "10.1016/j.bmcl.2014.05.056",

language = "English",

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T1 - Pentapeptide boronic acid inhibitors of Mycobacterium tuberculosis MycP1 protease

AU - Frasinyuk, Mykhaylo S.

AU - Kwiatkowski, Stefan

AU - Wagner, Jonathan M.

AU - Evans, Timothy J.

AU - Reed, Robert W.

AU - Korotkov, Konstantin V.

AU - Watt, David S.

N1 - Funding Information: D.S.W. was supported by the Office of the Dean of the College of Medicine and by NIH Grant Number P20 RR020171 from the National Institute of General Medical Sciences to L. Hersh, PI. K.V.K. was supported by the NIH/NIGMS Grant P20GM103486 . The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

PY - 2014/8/1

Y1 - 2014/8/1

N2 - 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 MycP 1msm 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.

AB - 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 MycP 1msm 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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KW - Pentapeptide

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