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      Target 2035 – update on the quest for a probe for every protein

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      RSC Medicinal Chemistry
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          Abstract

          Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

          Abstract

          Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. Target 2035 aims to develop a pharmacological modulator for every protein in the human proteome to fill this gap.

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          Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

          Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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            The FAIR Guiding Principles for scientific data management and stewardship

            There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders—representing academia, industry, funding agencies, and scholarly publishers—have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community.
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              Structure of Mpro from COVID-19 virus and discovery of its inhibitors

              A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
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                Author and article information

                Journal
                RSC Med Chem
                RSC Med Chem
                MD
                RMCSCX
                RSC Medicinal Chemistry
                RSC
                2632-8682
                3 December 2021
                27 January 2022
                3 December 2021
                : 13
                : 1
                : 13-21
                Affiliations
                [a] Institute of Pharmaceutical Chemistry, Goethe University Frankfurt Frankfurt 60438 Germany
                [b] Structural Genomics Consortium, BMLS, Goethe University Frankfurt Frankfurt 60438 Germany susanne.mueller-knapp@ 123456bmls.de
                [c] Structural Genomics Consortium, University of Toronto Toronto Ontario M5G 1L7 Canada Cheryl.Arrowsmith@ 123456uhnresearch.ca
                [d] University of Toronto Toronto Ontario M5G 1L7 Canada
                [e] Department of Data Science, The Institute of Cancer Research London SM2 5NG UK
                [f] CRUK ICR/Imperial Convergence Science Centre London SM2 5NG UK
                [g] Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research London SM2 5NG UK
                [h] Monash Institute of Pharmaceutical Sciences, Monash University Parkville Victoria 3052 Australia
                [i] School of Pharmaceutical Sciences, Nanjing Tech University No. 30 South Puzhu Road Nanjing 211816 People's Republic of China
                [j] Research and Development, Bayer AG, Pharmaceuticals 42103 Wuppertal Germany
                [k] Centre for Medicines Discovery, University of Oxford Old Road Campus Research Building, Roosevelt Drive Oxford OX3 7DQ UK
                [l] Merck KGaA Darmstadt Germany
                [m] Alzheimer's Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, University of Oxford Oxford OX3 7FZ UK
                [n] Institut Recherches de Servier 125 Chemin de Ronde 78290 Croissy France
                [o] Discovery Research, Boehringer Ingelheim 55216 Ingelheim am Rhein Germany
                [p] Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University Montreal QC Canada
                [q] School of Life Sciences, Division of Biological Chemistry and Drug Discovery, University of Dundee James Black Centre Dundee UK
                [r] Structural Genomics Consortium, UNC Eshelman School of Pharmacy Chapel Hill NC USA
                [s] Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA
                [t] Structural Genomics Consortium, Department of Medicine, Karolinska University Hospital and Karolinska Institutet Stockholm Sweden
                [u] Nuvisan Innovation Campus Berlin GmbH Müllerstraße 178 13353 Berlin Germany
                [v] Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA
                [w] Institute for Protein Innovation Boston MA USA
                [x] National Center for Advancing Translational Sciences, National Institutes of Health Rockville Maryland 20850 USA
                [y] Medicinal Chemistry, Global R&D, Merck Healthcare KGaA Frankfurter Straße 250 64293 Darmstadt Germany
                [z] Takeda California 9625 Towne Centre Drive San Diego California 92121 USA
                [aa] Science for Life Laboratory, Department of Oncology-Pathology Karolinska Institutet Stockholm Sweden
                [ab] Institute of Bioinformatics and Department of Biochemistry and Molecular Biology, University of Georgia Athens GA USA
                [ac] Genentech, Inc. 1 DNA Way South San Francisco California 94080 USA
                [ad] Department of Cancer Biology and Chemical Biology Program, Dana-Farber Cancer Institute 450 Brookline Ave Boston MA 02215 USA
                [ae] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria
                [af] European Molecular Biology Laboratory, European Bioinformatics Institute Wellcome Genome Campus, Hinxton Cambridgeshire CB10 1SD UK
                [ag] Strategic Innovation, Global R&D, Merck Healthcare KGaA Frankfurter Straße 250 64293 Darmstadt Germany
                [ah] Kennedy Institute of Rheumatology, NDORMS, University of Oxford UK
                [ai] Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan
                [aj] Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health Frederick MD USA
                [ak] LMU Munich, Department of Pharmacy, Chair of Pharmaceutical and Medicinal Chemistry 81377 Munich Germany
                [al] Discovery Network Group, Pfizer Medicine Design Cambridge MA 02139 USA
                [am] Drugs for Neglected Diseases initiative 15 Chemin Camille Vidart Geneva 1202 Switzerland
                [an] AbbVie North Chicago Illinois USA
                [ao] Global Research Externalization, Takeda California, Inc. 9625 Towne Center Drive San Diego CA 92121 USA
                [ap] Department of Pharmacology & Toxicology, University of Toronto Toronto Ontario M5S 1A8 Canada
                [aq] Research and Development, Bayer AG, Pharmaceuticals 13353 Berlin Germany
                [ar] Structural & Protein Sciences, Discovery Sciences, Janssen Research & Development 1400 McKean Rd Spring House PA 19477 USA
                [as] Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet Stockholm Sweden
                [at] Center for Physiology and Pharmacology, Medical University of Vienna Vienna Austria
                [au] School of Pharmacy, University College London London WC1N 1AX UK
                [av] Diamond Light Source Ltd Harwell Science and Innovation Campus Didcot OX11 0QX UK
                [aw] Department of Biochemistry, University of Johannesburg Auckland Park 2006 South Africa
                [ax] Research Complex at Harwell Harwell Science and Innovation Campus Didcot OX11 0FA UK
                [ay] Princess Margaret Cancer Centre Toronto Ontario M5G 1L7 Canada
                Author information
                https://orcid.org/0000-0003-2402-4157
                https://orcid.org/0000-0003-2114-8242
                https://orcid.org/0000-0002-8950-7646
                https://orcid.org/0000-0002-9705-0754
                https://orcid.org/0000-0002-8654-1670
                https://orcid.org/0000-0001-8750-679X
                https://orcid.org/0000-0002-7003-2812
                https://orcid.org/0000-0002-0885-6175
                https://orcid.org/0000-0002-0537-7101
                https://orcid.org/0000-0002-4784-6113
                https://orcid.org/0000-0001-6715-4213
                https://orcid.org/0000-0001-7096-4751
                https://orcid.org/0000-0002-0574-0169
                Article
                d1md00228g
                10.1039/d1md00228g
                8792830
                35211674
                acb5f702-c21f-4993-9c83-bcaeb8c50380
                This journal is © The Royal Society of Chemistry
                History
                : 6 July 2021
                : 21 September 2021
                Page count
                Pages: 9
                Funding
                Funded by: Chordoma Foundation, doi 10.13039/100009272;
                Award ID: Unassigned
                Funded by: Genome Canada, doi 10.13039/100008762;
                Award ID: OGI-196
                Funded by: National Cancer Institute, doi 10.13039/100000054;
                Award ID: T32 CA236754
                Funded by: Mark Foundation For Cancer Research, doi 10.13039/100014599;
                Award ID: Unassigned
                Funded by: Innovative Medicines Initiative, doi 10.13039/501100010767;
                Award ID: 875510
                Funded by: Cancer Research UK, doi 10.13039/501100000289;
                Award ID: C309/A11566
                Award ID: C35696/A23187
                Funded by: Seventh Framework Programme, doi 10.13039/100011102;
                Award ID: 600388
                Funded by: Wellcome Trust, doi 10.13039/100004440;
                Award ID: 204735/Z/16/Z
                Award ID: 212969/Z/18/Z
                Funded by: Agència per a la Competitivitat de l'Empresa, doi 10.13039/501100006253;
                Award ID: Unassigned
                Funded by: European Molecular Biology Laboratory, doi 10.13039/100013060;
                Award ID: Unassigned
                Categories
                Chemistry
                Custom metadata
                Paginated Article

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