Drug Discovery Strategies for SARS-CoV-2

Shyr, Zeenat A.; Gorshkov, Kirill; Chen, Catherine Z.; Zheng, Wei

doi:10.1124/jpet.120.000123

Cited by 97 publications

(88 citation statements)

References 106 publications

(166 reference statements)

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“…Common targets are viral enzymes such as viral protease, DNA and RNA polymerases, reverse transcriptase, and integrase. Development of assays targeting viral enzymes rely on viral enzyme expression, purification, assay development, and validation (Shyr et al, 2020). Alternatively, phenotypic assays involving live virus infections are readily executed once the viruses are isolated from patients and viral replication in appropriate host cells are established.…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Chen

Shinn

Itkin

et al. 2020

Preprint

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Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.

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Section: Discussionmentioning

confidence: 99%

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Chen

Shinn

Itkin

et al. 2020

Preprint

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“…As of early 2021, the zoonotic coronavirus disease 2019 (COVID-19) has infected over 98 million people, causing over 2 million deaths and imposing worldwide lockdowns ( https://coronavirus.jhu.edu/ ) ( Guan et al, 2020 ; Lam et al, 2020 ; Zhou et al, 2020 ). The search for effective antiviral therapies to treat COVID-19 has been broad and varied, ranging from repurposing known FDA-approved drugs to de novo fragment-based drug discovery ( Omolo et al, 2020 ; Shyr et al, 2020 ; Touret et al, 2020 ). An intermediate option in this arsenal of drug development applies existing inhibitor development pipelines from human disease targets to viral homologues.…”

Section: Introductionmentioning

confidence: 99%

Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors

Brosey¹,

Houl²,

Katsonis³

et al. 2021

Progress in Biophysics and Molecular Biology

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Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.

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“…Bei SARS-CoV‑2 handelt es sich um ein umhülltes [+]-ssRNA(positiv einzelsträngige Ribonukleinsäure)-Virus. Der Infektionsweg läuft hierbei in fünf Schritten ab [ 1 – 3 ] (s. auch Abb. 1 ).…”

Section: Allgemeine Informationenunclassified

Abstriche auf SARS-CoV-2 bei Tracheostomaträgern

Lochbaum

Hoffmann

Goldberg‐Bockhorn

2021

HNO

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Der Nachweis der Infektion mit dem "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) markierte Ende 2019 den Beginn einer globalen Pandemie. Im Rahmen der Pandemieeindämmung spielt der rasche und zuverlässige Nachweis des Virus eine entscheidende Rolle. Dieser erfolgt direkt aus Schleimhautabstrichen des Naso-oder Oropharynx. Da die Atmung bei Tracheostomaträgern nicht mehr über Rachen und Nase erfolgt, sondern über das Tracheostoma, stellt sich die Frage, ob hier das gleiche Verfahren gewählt werden kann.

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Drug Discovery Strategies for SARS-CoV-2

Abstract: ARDS Acute respiratory distress syndrome BSL Biosafety level 3CLpro 3C-like serine protease COVID-19 Coronavirus disease 2019 This article has not been copyedited and formatted. The final version may differ from this version.

Cited by 97 publications

References 106 publications

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors

Abstriche auf SARS-CoV-2 bei Tracheostomaträgern

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