About: A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors

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Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors
Creator	Liu, Jin Sankaran, Banumathi Yang, Kai Li, Pingwei Tseng, Chien-Te Drelich, Aleksandra Fierke, Carol Geng, Zhi Hsu, Jason Kratch, Kaci Liu, Wenshe Vatansever, Erol Xu, Shiqing Alugubelli, Yugendar Blankenship, Lauren Hayatshahi, Hamed Ma, Xinyu Ma, Yuying Scott, Danielle Sheng, Yan Ward, Hannah Zhao, Baoyu
Source	BioRxiv; Medline
abstract	The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replication in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active site cysteine C145. All inhibitors display high potency with IC50 values at or below 100 nM. The most potent compound MPI3 has as an IC50 value as 8.5 nM. Crystallographic analyses of SC2MPro bound to 7 inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549 cells. Two inhibitors MP5 and MPI8 completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with extreme potency. Due to the urgent matter of the COVID-19 pandemic, MPI5 and MPI8 may be quickly advanced to preclinical and clinical tests for COVID-19.
has issue date	2020-07-28(xsd:dateTime)
bibo:doi	10.1101/2020.07.28.223784
bibo:pmid	32766582
has license	biorxiv
sha1sum (hex)	7def6236b8c22d48bf70ff03ec9406012ece2a4d
schema:url	https://doi.org/10.1101/2020.07.28.223784
resource representing a document's title	A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors
has PubMed identifier	32766582
schema:publication	bioRxiv
resource representing a document's body	covid:7def6236b8c22d48bf70ff03ec9406012ece2a4d#body_text
is schema:about of	named entity 'virus' named entity 'digest' named entity 'Virus' named entity 'process' named entity 'COVID-19' named entity 'formation' named entity 'Protease Inhibitors' named entity 'MOLECULES' named entity 'ABOUT' named entity 'POLYPEPTIDES' named entity 'IC50' named entity 'INHIBITION' named entity 'PRO' named entity 'MEDICINAL CHEMISTRY' named entity 'ESSENTIAL' named entity 'CYSTEINE' named entity 'REVERSIBLE' named entity 'CHEMISTRY STUDIES' named entity 'VERO' named entity 'INVESTIGATIONS' named entity 'SARS-COV-1' named entity 'HIGH' named entity 'translated' named entity 'synthesized' named entity 'study' named entity 'Two' named entity 'IC50' named entity 'induced' named entity 'molecules' named entity 'Crystallographic' named entity 'Our' named entity 'inhibiting' named entity 'SARS-CoV-2' named entity 'preventing' named entity 'Vero' named entity 'covalent bond' named entity 'SARS-CoV-2' named entity 'protease' named entity 'IC50' named entity 'Crystallographic' named entity 'cytopathogenic effect' named entity 'cysteine' named entity 'Virus' named entity 'pathogenesis' named entity 'SARS-CoV-2' named entity 'enzyme' named entity 'protease' named entity 'virion' named entity 'amide' named entity 'aldehyde' named entity 'Coronaviruses' named entity 'MPI2' named entity 'Nsp5' named entity 'apoenzyme' named entity 'SARS-CoV-2' named entity 'MPI2' named entity '10 nM' named entity 'MERS-CoV' named entity 'protein' named entity 'X-ray diffraction' named entity 'proteolytic cleavage'

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