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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (6)

NSP3 (2)

ProteinS (1)

ProteinN (1)

ComplexRdRp (1)


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SARS-CoV-2 Proteins
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    ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin- like cysteine protease PROTEIN inhibitor exhibits in vivo efficacy in a Syrian Hamster model

    Authors: Koen Vandyck; Rana Abdelnabi; Kusum Gupta; Dirk Jochmans; Andreas Jekle; Jerome Deval; Dinah Misner; Dorothée Bardiot; Caroline S. Foo; Cheng Liu; Suping Ren; Leonid Beigelman; Lawrence M. Blatt; Sandro Boland; Laura Vangeel; Steven Dejonghe; Patrick Chaltin; Arnaud Marchand; Vladimir Serebryany; Antitsa Stoycheva; Sushmita Chanda; Julian A. Symons; Pierre Raboisson; Johan Neyts

    doi:10.1101/2021.02.14.431129 Date: 2021-02-15 Source: bioRxiv

    There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic MESHD. The SARS-CoV-2 main protease PROTEIN ( 3CLpro PROTEIN) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro PROTEIN inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro PROTEIN (IC50 = 7 nM) without affecting the activity of human cathepsin L HGNC (IC50 > 10 M). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log10 (RNA copies/mg) reduction of the viral RNA copies and 3.7 log10 (TCID50/mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro PROTEIN as a promising therapeutic target for selective small molecule inhibitors.

    Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

    Authors: Anneliese Ashhurst; Arthur Tang; Pavla Fajtova; Michael Yoon; Anupriya Aggarwal; Alexander Stoye; Mark Larance; Laura Beretta; Aleksandra Drelich; Danielle Skinner; Linfeng Li; Thomas Meek; James McKerrow; Vivian Hook; Chien-Te Tseng; Stuart Grant Turville; William Gerwick; Richard J Payne; Myra Hosmillo; Malte L Pinckert; Iliana Georgana; Anna Yakovleva; Laura G Caller; Sarah L Caddy; Theresa Feltwell; Fahad A Khokhar; Charlotte J Houldcroft; Martin D Curran; Surendra Parmar; - The COVID-19 Genomics UK (COG-UK) Consortium; Alex Alderton; Rachel Nelson; Ewan Harrison; John Sillitoe; Stephen D Bentley; Jeffrey C Barrett; M. Estee Torok; Ian G Goodfellow; Cordelia Langford; Dominic Kwiatkowski; - Wellcome Sanger Institute COVID-19 Surveillance Team

    doi:10.1101/2020.12.23.424111 Date: 2020-12-25 Source: bioRxiv

    The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic MESHD COVID-19 pandemic MESHD, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L HGNC is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L HGNC activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B HGNC and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro PROTEIN and PLpro PROTEIN. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection MESHD in vitro, with EC50 values in the nanomolar range, thus further highlighting the potential of cathepsin L HGNC as a COVID-19 MESHD antiviral drug target.

    Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19 MESHD

    Authors: Kas Steuten; Heeyoung Kim; John C. Widen; Brett M. Babin; Ouma Onguka; Scott Lovell; Oguz Bolgi; Berati Cerikan; Mirko Cortese; Ryan K. Muir; John M. Bennett; Ruth Geiss-Friedlander; Christoph Peters; Ralf Bartenschlager; Matthew Bogyo; Nuria Izquierdo-Useros; Roger Paredes; Lourdes Mateu; Anna Chamorro; Marta Massanella; Jorge Carrillo; Bonaventura Clotet; Julià Blanco; Benjamin Pinsky; Manisha Desai; Julie Parsonnet; Upinder Singh

    doi:10.1101/2020.11.21.392753 Date: 2020-11-23 Source: bioRxiv

    Two proteases produced by the SARS-CoV-2 virus, Mpro PROTEIN and PLpro PROTEIN, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19 MESHD. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro PROTEIN and PLpro PROTEIN proteases. These efforts identified a small number of hits for the Mpro PROTEIN protease and no viable hits for the PLpro PROTEIN protease. Of the Mpro PROTEIN hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2 HGNC, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mpro PROTEIN inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro PROTEIN inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L HGNC and B and showed similar loss in activity in cells expressing TMPRSS2 HGNC. Our results highlight the challenges of targeting Mpro PROTEIN and PLpro PROTEIN proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.

    Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses in cell culture

    Authors: Yanmei Hu; Chunlong Ma; Tommy Szeto; Brett Hurst; Bart Tarbet; Jun Wang; Meiling Zhang; Jiangtao Liu; Bin Pei; Aiguo Zhang; Chuanyi M Lu; Michael Y. Sha; A. John Iafrate

    doi:10.1101/2020.10.30.362335 Date: 2020-11-01 Source: bioRxiv

    As the COVID-19 pandemic MESHD COVID-19 pandemic MESHD continues to fold out, the morbidity and mortality are increasing daily. Effective treatment for SARS-CoV-2 is urgently needed. We recently discovered four SARS-CoV-2 main protease PROTEIN ( Mpro PROTEIN) inhibitors including boceprevir, calpain inhibitors II and XII and GC-376 with potent antiviral activity against infectious SARS-CoV-2 in cell culture. Despite the weaker enzymatic inhibition of calpain inhibitors II and XII against Mpro PROTEIN compared to GC-376, calpain inhibitors II and XII had more potent cellular antiviral activity. This observation promoted us to hypothesize that the cellular antiviral activity of calpain inhibitors II and XII might also involve the inhibition of cathepsin L HGNC in addition to Mpro PROTEIN. To test this hypothesis, we tested calpain inhibitors II and XII in the SARS-CoV-2 pseudovirus neutralization assay in Vero E6 cells and found that both compounds significantly decreased pseudoviral particle entry into cells, indicating their role in inhibiting cathepsin L. The involvement of cathepsin L was further confirmed in the drug time-of-addition experiment. In addition, we found that these four compounds not only inhibit SARS-CoV-2, but also SARS-CoV MESHD, MERS-CoV, as well as human coronaviruses (CoVs) 229E, OC43, and NL63. The mechanism of action is through targeting the viral Mpro PROTEIN, which was supported by the thermal shift binding assay and enzymatic FRET assay. We further showed that these four compounds have additive antiviral effect when combined with remdesivir. Altogether, these results suggest that boceprevir, calpain inhibitors II and XII, and GC-376 are not only promising antiviral drug candidates against existing human coronaviruses, but also might work against future emerging CoVs.

    Discovery of Natural Phenol Catechin as a Multitargeted Agent Against SARS-CoV-2 For the Plausible Therapy of COVID-19 MESHD

    Authors: Chandra Bhushan Mishra; Preeti Pandey; Ravi Datta Sharma; Raj Kumar Mongre; Andrew M Lynn; Rajendra Prasad; Raok Jeon; Amresh Prakash

    doi:10.26434/chemrxiv.12752402.v1 Date: 2020-08-04 Source: ChemRxiv

    The global pandemic crisis, COVID-19 MESHD caused by severe acute respiratory syndrome coronavirus MESHD 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines, are not turned to be realistic in the timeframe needed to combat this pandemic. Thus, rigorous efforts are still ongoing for the drug repurposing as a clinical treatment strategy to control COVID-19 MESHD. Here we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, which are crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 72 FDA approved potential antiviral drugs against the target proteins: Spike (S PROTEIN) glycoprotein, human angiotensin-converting enzyme 2 ( hACE2 HGNC), 3-chymotrypsin- like cysteine protease PROTEIN ( 3CLpro PROTEIN), Cathepsin L HGNC, Nucleocapsid protein PROTEIN, RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) and nonstructural protein 6 ( NSP6 PROTEIN) resulted in the selection of seven drugs which preferentially binds to the target proteins. Further, the molecular interactions determined by MD simulation, free energy landscape and the binding free energy estimation, using MM-PBSA revealed that among 72 drug molecules, catechin (flavan-3-ol) can effectively bind to 3CLpro PROTEIN, Cathepsin L HGNC, RBD of S protein PROTEIN, NSP-6, and Nucleocapsid protein PROTEIN. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol ( Cathepsin L HGNC) to -26.09 kcal/mol ( NSP6 PROTEIN). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favourable molecular interaction of catechin towards multiple target proteins, signifies that catechin can be potentially explored as a multitargeted agent in the rational design of effective therapies against COVID-19 MESHD.

    Structure and inhibition of the SARS-CoV-2 main protease PROTEIN reveals strategy for developing dual inhibitors against Mpro PROTEIN and cathepsin L

    Authors: Michael Dominic Sacco; Chunlong Ma; Panagiotis Lagarias; Ang Gao; Julia Alma Townsend; Xiangzhi Meng; Peter Dube; Xiujun Zhang; Yanmei Hu; Naoya Kitamura; Brett Hurst; Bart Tarbet; Michael Thomas Marty; Antonios Kolocouris; Yan Xiang; Yu Chen; Jun Wang

    doi:10.1101/2020.07.27.223727 Date: 2020-07-27 Source: bioRxiv

    The main protease PROTEIN ( Mpro) of SARS-CoV-2 PROTEIN, the pathogen responsible for the COVID-19 pandemic MESHD COVID-19 pandemic MESHD, is a key antiviral drug target. While most SARS-CoV-2 Mpro PROTEIN inhibitors have a {gamma}-lactam glutamine surrogate at the P1 position, we recently discovered several Mpro PROTEIN inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L HGNC, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of Mpro PROTEIN in complex with calpain inhibitors II and XII, and three analogues of GC-376, one of the most potent Mpro PROTEIN inhibitors in vitro. The structure of Mpro PROTEIN with calpain inhibitor II confirmed the S1 pocket of Mpro PROTEIN can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose where the P1 pyridine inserts in the S1 pocket and the P1 norvaline is positioned in the S1 pocket. The overall conformation is semi-helical, wrapping around the catalytic core, in contrast to the extended conformation of other peptidomimetic inhibitors. Additionally, the structures of three GC-376 analogues UAWJ246, UAWJ247, and UAWJ248 provide insight to the sidechain preference of the S1, S2, S3 and S4 pockets, and the superior cell-based activity of the aldehyde warhead compared with the -ketoamide. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of Mpro PROTEIN inhibitors as SARS-CoV-2 antivirals.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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