title: Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: structure-activity relationship study.
abstract: This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CL(pro). In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1' position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
authors.forename: Pillaiyar
authors.initials: P
authors.lastname: Thanigaimalai
authors.forename: Sho
authors.initials: S
authors.lastname: Konno
authors.forename: Takehito
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koiwai
authors.forename: Akihiro
authors.initials: A
authors.lastname: Taguchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takayama
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akaji
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.forename: Aurash
authors.initials: A
authors.lastname: Naser-Tavakolian
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases
keywords: Cysteine protease inhibitors; Dipeptide; Docking study; Peptidomimetics; SARS; SARS-CoV 3CL protease