6vkd
From Proteopedia
Crystal Structure of Inhibitor JNJ-36689282 in Complex with Prefusion RSV F Glycoprotein
Structural highlights
FunctionM1E1E4_9HIV1 FUS_HRSVA Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.[1] [2] Publication Abstract from PubMedRespiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor which showed to be efficacious in a phase 2a challenge study in healthy adult subjects and which is currently being evaluated in hospitalized infants and adults. Co-crystal structures of several new derivatives helped rationalizing some of the structure activity relationship (SAR) trends observed. Discovery of 3 ({5 Chloro-1 [3 (methylsulfonyl)propyl]-1H indol-2 yl}methyl)-1 (2,2,2 trifluoroethyl)-1,3 dihydro-2H imidazo[4,5-c]pyridin-2 one (JNJ-53718678), a potent and orally bioavailable fusion inhibitor of respiratory syncytial virus.,Vendeville S, Tahri A, Hu L, Demin S, Cooymans L, Vos A, Kwanten L, Van den Berg J, Battles M, McLellan J, Koul A, Raboisson P, Roymans D, Jonckers THM J Med Chem. 2020 May 14. doi: 10.1021/acs.jmedchem.0c00226. PMID:32407115[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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