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      Kinase Inhibitors as Underexplored Antiviral Agents

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          Abstract

          Viral infections are a major health problem; therefore, there is an urgent need for novel therapeutic strategies. Antivirals used to target proteins encoded by the viral genome usually enhance drug resistance generated by the virus. A potential solution may be drugs acting at host-based targets since viruses are dependent on numerous cellular proteins and phosphorylation events that are crucial during their life cycle. Repurposing existing kinase inhibitors as antiviral agents would help in the cost and effectiveness of the process, but this strategy usually does not provide much improvement, and specific medicinal chemistry programs are needed in the field. Anyway, extensive use of FDA-approved kinase inhibitors has been quite useful in deciphering the role of host kinases in viral infection. The present perspective aims to review the state of the art of kinase inhibitors that target viral infections in different development stages.

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          Most cited references186

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

            Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells 1,2 . Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2) 3,4 , isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV. Supplementary information The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.
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              The protein kinase complement of the human genome.

              G. Manning (2002)
              We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
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                Author and article information

                Journal
                J Med Chem
                J Med Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                10 May 2021
                27 January 2022
                : 65
                : 2 , New Horizons in Drug Discovery - Understanding and Advancing Kinase Inhibitors
                : 935-954
                Affiliations
                Centro de Investigaciones Biológicas Margarita Salas (CSIC) , Ramiro de Maeztu 9, 28040 Madrid, Spain
                Author notes
                [* ](A.M.) E-mail: ana.martinez@ 123456csic.es .
                [* ](C.G.) E-mail: carmen.gil@ 123456csic.es .
                Article
                10.1021/acs.jmedchem.1c00302
                8802305
                33970631
                eb7a49d4-4c52-4603-b237-27a3fbdcbad7
                © 2021 American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                Funding
                Funded by: “la Caixa” Foundation, doi 10.13039/100010434;
                Award ID: LCF/PR/HR19/52160012
                Funded by: Ministerio de Ciencia e Innovación, doi 10.13039/501100004837;
                Award ID: PID2019-105600RB-I00
                Funded by: Consejo Superior de Investigaciones Científicas, doi 10.13039/501100003339;
                Award ID: JAEINT_20_01339
                Funded by: Consejo Superior de Investigaciones Científicas, doi 10.13039/501100003339;
                Award ID: 202080E293
                Funded by: Consejo Superior de Investigaciones Científicas, doi 10.13039/501100003339;
                Award ID: 202020E103
                Categories
                Perspective
                Custom metadata
                jm1c00302
                jm1c00302

                Pharmaceutical chemistry
                Pharmaceutical chemistry

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