title: Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.
abstract: We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
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: 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; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases
keywords: Cysteine protease inhibitors; Dipeptide; Peptidomimetics; SARS; SARS-CoV 3CL(pro)