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Inhibitors of Protein-Protein Interactions in Paramyxovirus Fusion: A Focus on Respiratory Syncytial Virus Nicholas A. Meanwell and David R. Langley
Contents 1 2 3 4 5
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiratory Syncytial Virus: Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiratory Syncytial Virus Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibitors of Respiratory Syncytial Virus Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibitors of Respiratory Syncytial Virus Fusion: Interfering with an Intramolecular Protein-Protein Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The assembly of the N-terminus heptad repeats of the respiratory syncytial virus (RSV) F protein into a trimeric complex that associates with the C-terminus heptad repeats to form a six-helix bundle is a critical step in the process of virus-host fusion and represents an intramolecular protein-protein interaction. Screening campaigns using replicating virus assays have identified several structurally distinct but mechanistically similar chemotypes that interfere with RSV fusion by disrupting the function of the F protein six-helix bundle. This chapter summarizes structure-activity relationships and mechanistic insights associated with the most prominent RSV fusion inhibitors and the key issues in the development of potential clinical candidates. Keywords Inhibitors • Protein-protein interaction • Respiratory syncytial virus
N.A. Meanwell (*) Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA e-mail: [email protected] D.R. Langley Department of Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA 167
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N.A. Meanwell and D.R. Langley
1 Introduction Fundamental aspects of the mechanics of virus fusion processes have been elucidated by a combination of extensive biochemical studies, experimental observations with inhibitors of fusion and X-ray crystallographic data of fusion proteins in their native and postfusion states [1–7]. A key step in respiratory syncytial virus (RSV) fusion that is common to many viruses involves a significant rearrangement of the fusion protein, a process that unmasks a hydrophobic 10–12 residue fusion peptid
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