Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.
We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
Ghosh
Arun K
AK
Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA. akghosh@purdue.edu
Takayama
Jun
J
Aubin
Yoann
Y
Ratia
Kiira
K
Chaudhuri
Rima
R
Baez
Yahira
Y
Sleeman
Katrina
K
Coughlin
Melissa
M
Nichols
Daniel B
DB
Mulhearn
Debbie C
DC
Prabhakar
Bellur S
BS
Baker
Susan C
SC
Johnson
Michael E
ME
Mesecar
Andrew D
AD
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D015195:Drug Design; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D001549:Benzamides; C550443:N-methyl-5-methylamino-2-methyl-N-((R)-1-(1-naphthyl)ethy)benzamide; D009281:Naphthalenes; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases