Functional and druggability analysis of the SARS-CoV-2 proteome
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Abstract
The infectious coronavirus disease (COVID-19) pandemic, caused by the coronavirus SARS-CoV-2, appeared in December 2019 in Wuhan, China, and has spread worldwide. As of today, more than 22 million people have been infected, with almost 800,000 fatalities. With the purpose of contributing to the development of effective therapeutics, this work provides an overview of the viral machinery and functional role of each SARS-CoV-2 protein, and a thorough analysis of the structure and druggability assessment of the viral proteome. All structural, non-structural, and accessory proteins of SARS-CoV-2 have been studied, and whenever experimental structural data of SARS-CoV-2 proteins were not available, homology models were built based on solved SARS-CoV structures. Several potential allosteric or protein-protein interaction druggable sites on different viral targets were identified, knowledge that could be used to expand current drug discovery endeavors beyond the cysteine proteases and the polymerase complex. It is our hope that this study will support the efforts of the scientific community both in understanding the molecular determinants of this disease and in widening the repertoire of viral targets in the quest for repurposed or novel drugs against COVID-19.
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SciScore for 10.1101/2020.08.21.261404: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, protease inhibitors might lack selectivity [24], and the efficacy of nucleoside inhibitors targeting the RdRp is limited by the ExoN proofreading machine and non-mutagenic doses limitations, and thus alternative or complementary therapeutic strategies to fight COVID-19 are needed. In this work we stress the fact that besides the replicative and structural proteins, all of which are critical for the viral cycle, other proteins also have …
SciScore for 10.1101/2020.08.21.261404: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, protease inhibitors might lack selectivity [24], and the efficacy of nucleoside inhibitors targeting the RdRp is limited by the ExoN proofreading machine and non-mutagenic doses limitations, and thus alternative or complementary therapeutic strategies to fight COVID-19 are needed. In this work we stress the fact that besides the replicative and structural proteins, all of which are critical for the viral cycle, other proteins also have vital functions, and thus would constitute excellent targets for drug discovery. The helicase (nsp13), and methyl-transferases N7-Mtase (nsp14) and 2′-O-MTase (nsp16) contribute to genome stability through their involvement in the capping process; the ExoN (nsp14) is responsible for proofreading, and thus for the extremely low mutation rate and nucleoside analogs resistanse of SARS-CoV-2; several nsp3 domains, such as SUD, NAB and Ub1 are known to bind ssRNA; the NendoU (nsp15) cleaves polyuridines produced during the priming of the poly(A) ssRNA during replication, which helps to dampen dsRNA MDA5-dependent antiviral IFN responses [125]; nsp9 acts as a hub that binds ssRNA and interacts with nsp8, the N protein, and several host nuclear pore proteins [15,130,131]; the ADRP and PLpro attenuate the effects of IFN and cytokine signaling components that induce antiviral and inflammatory responses [54,142]; orf3a and orf7a induce NFκB, IL-8, and JNK, promoting inflammatory responses [198], while orf3a also induces the production of fibrino...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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