Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors

Bioorganic & Medicinal Chemistry
Volume 24, Issue 13, 1 July 2016, Pages 3035-3042

Vathan Kumar, Kian-Pin Tan, Ying-Ming Wang, Sheng-Wei Lin, Po-Huang Liang

Abstract

Severe acute respiratory syndrome (SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CLpro of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R1 or R4 destabilizes the oxyanion hole in the 3CLpro. Interestingly, 3f, 3g and 3m could inhibit both NA and 3CLpro and serve as a starting point to develop broad-spectrum antiviral agents.

Keywords

MERS-CoV, SARS-Cov, 3CLpro, Coronavirus, Pyrazolone

Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as (SARS-CoV) 3CLpro inhibitors...

Bioorganic & Medicinal Chemistry Letters
Volume 23, Issue 22, 15 November 2013, Pages 6172-6177

Mark Turlington, Aspen Chun, Sakshi Tomar, Aimee Eggler, Valerie Grum-Tokars, Jon Jacobs, J. Scott Daniels, Eric Dawson, Adrian Saldanha, Peter Chase, Yahira M. Baez-Santos, Craig W. Lindsley, Peter Hodder, Andrew D. Mesecar, Shaun R. Stauffer

Abstract

Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2–S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

Keywords

3CLpro, Severe acute respiratory syndrome, SARS, MERS, Coronavirus

Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases

Bioorganic & Medicinal Chemistry
Volume 20, Issue 19, 1 October 2012, Pages 5928-5935

Ji-Young Park, Jang Hoon Kim, Young Min Kim, Hyung Jae Jeong, Dae Wook Kim, Ki Hun Park, Hyung-Jun Kwon, Su-Jin Park, Woo Song Lee, Young Bae Ryu

Abstract

In the search for anti-SARS-CoV, tanshinones derived from Salvia miltiorrhiza were found to be specific and selective inhibitors for the SARS-CoV 3CLpro and PLpro, viral cysteine proteases. A literature search for studies involving the seven isolated tanshinone hits showed that at present, none have been identified as coronaviral protease inhibitors. We have identified that all of the isolated tanshinones are good inhibitors of both cysteine proteases. However, their activity was slightly affected by subtle changes in structure and targeting enzymes. All isolated compounds (1–7) act as time dependent inhibitors of PLpro, but no improved inhibition was observed following preincubation with the 3CLpro. In a detail kinetic mechanism study, all of the tanshinones except rosmariquinone (7) were identified as noncompetitive enzyme isomerization inhibitors. However, rosmariquinone (7) showed a different kinetic mechanism through mixed-type simple reversible slow-binding inhibition. Furthermore, tanshinone I (5) exhibited the most potent nanomolar level inhibitory activity toward deubiquitinating (IC50 = 0.7 μM). Additionally, the inhibition is selective because these compounds do not exert significant inhibitory effects against other proteases including chymotrysin, papain, and HIV protease. These findings provide potential inhibitors for SARS-CoV viral infection and replication.

Keywords

Tanshinone, SARS-CoV, 3CLpro, PLpro, Slow-binding inhibitor

SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii

Bioorganic & Medicinal Chemistry Letters
Volume 20, Issue 6, 15 March 2010, Pages 1873-1876

Young Bae Ryu, Su-Jin Park, Young Min Kim, Ju-Yeon Lee, Woo Duck Seo, Jong Sun Chang, Ki Hun Park, Mun-Chual Rho, Woo Song Lee

Abstract

Quinone-methide triterpenes, celastrol (1), pristimerin (2), tingenone (3), and iguesterin (4) were isolated from Triterygium regelii and dihydrocelastrol (5) was synthesized by hydrogenation under palladium catalyst. Isolated quinone-methide triterpenes (1–4) and 5 were evaluated for SARS-CoV 3CLpro inhibitory activities and showed potent inhibitory activities with IC50 values of 10.3, 5.5, 9.9, and 2.6 μM, respectively, whereas the corresponding 5 having phenol moiety was observed in low activity (IC50 = 21.7 μM). As a result, quinone-methide moiety in A-ring and more hydrophobic E-ring assist to exhibit potent activity. Also, all quinone-methide triterpenes 1–4 have proven to be competitive by the kinetic analysis.

Keyword

SARS-CoV, 3CLpro, Tripterygium regelii, Quinone-methide, Celastrol, Iguesterin

SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 6, 15 March 2010, Pages 1873-1876

Young Bae Ryu, Su-Jin Park, Young Min Kim, Ju-YeonLee, Woo Duck Seo, Jong SunChang, Ki Hun Park, Mun-Chual Rho, Woo Song Lee

Abstract

Quinone-methide triterpenes, celastrol (1), pristimerin (2), tingenone (3), and iguesterin (4) were isolated from Triterygium regelii and dihydrocelastrol (5) was synthesized by hydrogenation under palladium catalyst. Isolated quinone-methide triterpenes (1–4) and 5 were evaluated for SARS-CoV 3CLpro inhibitory activities and showed potent inhibitory activities with IC50 values of 10.3, 5.5, 9.9, and 2.6 μM, respectively, whereas the corresponding 5 having phenol moiety was observed in low activity (IC50 = 21.7 μM). As a result, quinone-methide moiety in A-ring and more hydrophobic E-ring assist to exhibit potent activity. Also, all quinone-methide triterpenes 1–4 have proven to be competitive by the kinetic analysis.

Keyword

SARS-CoV, 3CLpro, Tripterygium regelii, Quinone-methide, Celastrol, Iguesterin