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 journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Pages (from-to)3546-3548
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Issue number15
StatePublished - 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.


  • Boronic acid
  • Inhibitor
  • Pentapeptide
  • Protease

ASJC Scopus subject areas

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


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