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 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.
authors.affiliation: Institute of Bioorganic Chemistry and Petrochemistry, Kyiv-94 02660, Ukraine; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Mykhaylo S
authors.initials: MS
authors.lastname: Frasinyuk
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kwiatkowski
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wagner
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Evans
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Reed
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Korotkov
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA. Electronic address: dwatt@uky.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001897:Boronic Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D013381:Subtilisins; C471626:mycosin-1, Mycobacterium tuberculosis
keywords: Boronic acid; Inhibitor; Pentapeptide; Protease