JNJ-7184, a respiratory syncytial virus inhibitor targeting the connector domain of the viral polymerase
Brecht Bonneux, Afzaal Shareef, Sergey Tcherniuk, Brandon J. Anson, Suzanne De Bruyn, Nick Verheyen, Kim Thys, Nádia Conceição‐Neto, Marcia Van Ginderen, Leen Kwanten, Nina Ysebaert, Luc Vranckx, E. Peeters, Ellen Lanckacker, Jack M. Gallup, Panchan Sitthicharoenchai, Sarhad Alnajjar, Mark R. Ackermann, Suraj Adhikary, A. Bhaumik, Aaron Patrick, Amy Fung, Priscila Sutto‐Ortiz, Étienne Decroly, Stephen W. Mason, David Lançois, Jérôme Deval, Zhinan Jin, Jean‐François Eléouët, Rachel Fearns, Anil Koul, Dirk Roymans, Peter Rigaux, Florence Herschke
Abstract
Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.