Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an
            aza
            ‐decaline scaffold

AbstractWe report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.

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Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors

RSC Medicinal Chemistry ◽

10.1039/d1md00247c ◽

2021 ◽

Author(s):

Bing Bai ◽

Elena Arutyunova ◽

Muhammad Bashir Khan ◽

Jimmy Lu ◽

Michael A. Joyce ◽

...

Keyword(s):

Protease Inhibitors ◽

Direct Acting Antivirals ◽

Death Toll ◽

Direct Acting ◽

3Cl Protease

Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately...

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Synthesis of glutamic acid and glutamine peptides possessing a trifluoromethyl ketone group as SARS-CoV 3CL protease inhibitors

Tetrahedron ◽

10.1016/j.tet.2006.06.052 ◽

2006 ◽

Vol 62 (36) ◽

pp. 8601-8609 ◽

Cited By ~ 22

Author(s):

Magne O. Sydnes ◽

Yoshio Hayashi ◽

Vinay K. Sharma ◽

Takashi Hamada ◽

Usman Bacha ◽

...

Keyword(s):

Glutamic Acid ◽

Protease Inhibitors ◽

Ketone Group ◽

3Cl Protease

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Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2013.05.005 ◽

2013 ◽

Vol 65 ◽

pp. 436-447 ◽

Cited By ~ 19

Author(s):

Pillaiyar Thanigaimalai ◽

Sho Konno ◽

Takehito Yamamoto ◽

Yuji Koiwai ◽

Akihiro Taguchi ◽

...

Keyword(s):

Protease Inhibitors ◽

Structure Activity Relationship ◽

Biological Evaluation ◽

Activity Relationship ◽

Design Synthesis ◽

Structure Activity ◽

Relationship Study ◽

3Cl Protease ◽

Synthesis And Biological Evaluation

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Design and Synthesis of Cinanserin Analogs as Severe Acute Respiratory Syndrome Coronavirus 3CL Protease Inhibitors

Chemical and Pharmaceutical Bulletin ◽

10.1248/cpb.56.1400 ◽

2008 ◽

Vol 56 (10) ◽

pp. 1400-1405 ◽

Cited By ~ 17

Author(s):

Qingang Yang ◽

Lili Chen ◽

Xuchang He ◽

Zhenting Gao ◽

Xu Shen ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Protease Inhibitors ◽

Design And Synthesis ◽

3Cl Protease

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Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery

Biochemical Society Transactions ◽

10.1042/bst0391371 ◽

2011 ◽

Vol 39 (5) ◽

pp. 1371-1375 ◽

Cited By ~ 27

Author(s):

R. Ramajayam ◽

Kian-Pin Tan ◽

Po-Huang Liang

Keyword(s):

Drug Discovery ◽

Severe Acute Respiratory Syndrome ◽

Protease Inhibitors ◽

Therapeutic Agents ◽

3C Protease ◽

The World ◽

Structural Differences ◽

Life Threatening ◽

Dual Inhibitors ◽

3Cl Protease

SARS-CoV (severe acute respiratory syndrome-associated coronavirus) caused infection of ~8000 people and death of ~800 patients around the world during the 2003 outbreak. In addition, picornaviruses such as enterovirus, coxsackievirus and rhinovirus also can cause life-threatening diseases. Replication of picornaviruses and coronaviruses requires 3Cpro (3C protease) and 3CLpro (3C-like protease) respectively, which are structurally analogous with chymotrypsin-fold, but the former is a monomer and the latter is dimeric due to an extra third domain for dimerization. Subtle structural differences in the S2 and S3 pockets of these proteases make inhibitors selective, but some dual inhibitors have been discovered. Our findings as summarized in the present review provide new potential anti-coronavirus and anti-picornavirus therapeutic agents and a clue to convert 3CLpro inhibitors into 3Cpro inhibitors and vice versa.

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