Respiratory Syncytial Virus Two-Step Infection Screen Reveals Inhibitors of Early and Late Life Cycle Stages.

Autor:	Sake SM; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Kosch C; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Saarbrücken, Germany., Blockus S; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Haid S; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Gunesch AP; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Zhang X; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Friesland M; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Trummer SB; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Grethe C; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Kühnel A; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany., Rückert J; Institute of Virology, Hanover Medical Schoolgrid.10423.34, Hanover, Germany.; German Centre for Infection Research, Hanover-Braunschweig Site, Hanover, Germany., Duprex WP; Centre for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Huang J; Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorfgrid.13648.38, Hamburg, Germany., Rameix-Welti MA; Université Paris-Saclay, Université de Versailles St. Quentin, UMR 1173 (2I), INSERM, Assistance Publique des Hôpitaux de Paris, Hôpital Ambroise Paré, Laboratoire de Microbiologie, Versailles, France., Empting M; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Saarbrücken, Germany., Fischer N; Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorfgrid.13648.38, Hamburg, Germany., Hirsch AKH; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.; Department of Pharmacy, Saarland University, Saarbrücken, Germany.; Helmholtz International Lab for Anti-Infectives, Helmholtz Center for Infection Research, Braunschweig, Germany.; Cluster of Excellence RESIST (EXC 2155), Hanover Medical Schoolgrid.10423.34, Hanover, Germany., Schulz TF; Institute of Virology, Hanover Medical Schoolgrid.10423.34, Hanover, Germany.; German Centre for Infection Research, Hanover-Braunschweig Site, Hanover, Germany.; Cluster of Excellence RESIST (EXC 2155), Hanover Medical Schoolgrid.10423.34, Hanover, Germany., Pietschmann T; Institute for Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, Hanover, Germany.; German Centre for Infection Research, Hanover-Braunschweig Site, Hanover, Germany.; Helmholtz International Lab for Anti-Infectives, Helmholtz Center for Infection Research, Braunschweig, Germany.; Cluster of Excellence RESIST (EXC 2155), Hanover Medical Schoolgrid.10423.34, Hanover, Germany.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 Dec 20; Vol. 66 (12), pp. e0103222. Date of Electronic Publication: 2022 Nov 08.
DOI:	10.1128/aac.01032-22
Abstrakt:	Human respiratory syncytial virus (hRSV) infection is a leading cause of severe respiratory tract infections. Effective, directly acting antivirals against hRSV are not available. We aimed to discover new and chemically diverse candidates to enrich the hRSV drug development pipeline. We used a two-step screen that interrogates compound efficacy after primary infection and a consecutive virus passaging. We resynthesized selected hit molecules and profiled their activities with hRSV lentiviral pseudotype cell entry, replicon, and time-of-addition assays. The breadth of antiviral activity was tested against recent RSV clinical strains and human coronavirus (hCoV-229E), and in pseudotype-based entry assays with non-RSV viruses. Screening 6,048 molecules, we identified 23 primary candidates, of which 13 preferentially scored in the first and 10 in the second rounds of infection, respectively. Two of these molecules inhibited hRSV cell entry and selected for F protein resistance within the fusion peptide. One molecule inhibited transcription/replication in hRSV replicon assays, did not select for phenotypic hRSV resistance and was active against non-hRSV viruses, including hCoV-229E. One compound, identified in the second round of infection, did not measurably inhibit hRSV cell entry or replication/transcription. It selected for two coding mutations in the G protein and was highly active in differentiated BCi-NS1.1 lung cells. In conclusion, we identified four new hRSV inhibitor candidates with different modes of action. Our findings build an interesting platform for medicinal chemistry-guided derivatization approaches followed by deeper phenotypical characterization in vitro and in vivo with the aim of developing highly potent hRSV drugs.
Databáze:	MEDLINE
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