Advances in developing small molecule SARS 3CLpro inhibitors as potential remedy for corona virus infection

Konwar, Manashjyoti; Sarma, Diganta

doi:10.1016/j.tet.2020.131761

Cited by 24 publications

(17 citation statements)

References 130 publications

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“…Since 3CL pro is a cysteine protease, albeit with a fold related to the serine protease chymotrypsin, there is a good chance that specific inhibitors of this enzyme could be developed, making 3CL pro an important drug target for antivirals. These concepts have been pursued in the past for SARS-CoV 3CL pro (Pillaiyar et al, 2016), although the rapid disappearance of that virus decreased interest in such work, and they have now been proposed again (Konwar & Sarma, 2021).…”

Section: The Role and Significance Of 3cl Promentioning

confidence: 99%

Crystallographic models of SARS-CoV-2 3CL^pro: in-depth assessment of structure quality and validation

Jaskólski

Dauter

Shabalin

et al. 2021

Int Union Crystallogr J

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The appearance at the end of 2019 of the new SARS-CoV-2 coronavirus led to an unprecedented response by the structural biology community, resulting in the rapid determination of many hundreds of structures of proteins encoded by the virus. As part of an effort to analyze and, if necessary, remediate these structures as deposited in the Protein Data Bank (PDB), this work presents a detailed analysis of 81 crystal structures of the main protease 3CLpro, an important target for the design of drugs against COVID-19. The structures of the unliganded enzyme and its complexes with a number of inhibitors were determined by multiple research groups using different experimental approaches and conditions; the resulting structures span 13 different polymorphs representing seven space groups. The structures of the enzyme itself, all determined by molecular replacement, are highly similar, with the exception of one polymorph with a different inter-domain orientation. However, a number of complexes with bound inhibitors were found to pose significant problems. Some of these could be traced to faulty definitions of geometrical restraints for ligands and to the general problem of a lack of such information in the PDB depositions. Several problems with ligand definition in the PDB itself were also noted. In several cases extensive corrections to the models were necessary to adhere to the evidence of the electron-density maps. Taken together, this analysis of a large number of structures of a single, medically important protein, all determined within less than a year using modern experimental tools, should be useful in future studies of other systems of high interest to the biomedical community.

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Section: The Role and Significance Of 3cl Promentioning

confidence: 99%

Crystallographic models of SARS-CoV-2 3CL^pro: in-depth assessment of structure quality and validation

Jaskólski

Dauter

Shabalin

et al. 2021

Int Union Crystallogr J

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“…After the fusion of SARS-CoV-2 with the host cell, the viral RNA is released into the cytosol, which is translated into the replicase proteins [15]. 3CL pro and PL pro cleave the replicase polyprotein into 15-16 nonstructural proteins (nsps) at consensus cleavage sites [28,[39][40][41]. Some of these nsps encode proteins with essential functions for virus-mediated RNA replication, so targeting these proteins is an effective antiviral strategy for suppressing viral genome replication in order to cure CoV infection.…”

Section: C-like Protease and Papain-like Proteasementioning

confidence: 99%

“…The 3CL pro is a dimeric cysteine protease where each monomer contains one independent active site, rendering the monomers less active than the dimer. The active site is composed of a cysteine and a histidine, where the cysteine acts as a nucleophile and the histidine residue acts as a base [39][40][41]. The two replicase polyproteins (pp1a and pp1ab), also known as promoters, are packed at almost a right angle [41].…”

Section: C-like Protease and Papain-like Proteasementioning

confidence: 99%

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Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents

2021

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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 is not available yet. Moreover, since new and deadly CoVs can emerge at any time with the potential of becoming pandemics, the development of therapeutic agents against potentially deadly CoVs is a research area of much current interest. In the search for anti-coronaviral drugs, researchers soon turned their heads towards glycosylated flavonoids. Glycosyl flavonoids, widespread in the plant kingdom, have received a lot of attention due to their widely recognized antioxidant, anti-inflammatory, neuroprotective, anticarcinogenic, antidiabetic, antimicrobial, and antiviral properties together with their capacity to modulate key cellular functions. The wide range of biological activities displayed by glycosyl flavonoids, along with their low toxicity, make them ideal candidates for drug development. In this review, we examine and discuss the up-to-date developments on glycosyl flavonoids as evidence-based natural sources of antivirals against coronaviruses and their potential role in the management of COVID-19.

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“…SARS-CoV-2 3CLpro is therefore an attractive target for drug development. [16][17][18][19][20][21][22][23] We recently described the structure-guided design of a dipeptidyl series of MERS-CoV and SARS-CoV-2 3CLpro inhibitors incorporating in their structure a piperidine 11 or cyclohexyl 10 moiety capable of engaging in favorable binding interactions with the S4 pocket. We furthermore demonstrated that members of the cyclohexyl series of compounds improve survival in a mouse model of MERS-CoV infection.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

D.¹,

Perera²,

Jesri³

et al. 2021

Preprint

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Advances in developing small molecule SARS 3CLpro inhibitors as potential remedy for corona virus infection

Cited by 24 publications

References 130 publications

Crystallographic models of SARS-CoV-2 3CL^pro: in-depth assessment of structure quality and validation

Crystallographic models of SARS-CoV-2 3CL^pro: in-depth assessment of structure quality and validation

Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

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Advances in developing small molecule SARS 3CLpro inhibitors as potential remedy for corona virus infection

Cited by 24 publications

References 130 publications

Crystallographic models of SARS-CoV-2 3CLpro: in-depth assessment of structure quality and validation

Crystallographic models of SARS-CoV-2 3CLpro: in-depth assessment of structure quality and validation

Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

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Product

Resources

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Crystallographic models of SARS-CoV-2 3CL^pro: in-depth assessment of structure quality and validation

Crystallographic models of SARS-CoV-2 3CL^pro: in-depth assessment of structure quality and validation