Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection.
Human respiratory syncytial virus (hRSV) is a significant cause of respiratory illness in at-risk pediatric patients, immunocompromised adults and the elderly. No vaccine is currently available for the virus and treatment options are limited to the prophylactic treatment of at-risk infants with the mAb palivizumab (Synagis) and to therapeutic intervention with the nucleoside analog ribavirin (Rebetol). The clinical use of these agents is limited and a need exists for more effective treatment for the at-risk population. The merging of viral and cellular membranes is a crucial event in the hRSV life cycle that enables the virus to enter a host cell. The multistep fusion process is facilitated by the substantial refolding of a trimeric class I fusion protein (F protein), which is the main target of fusion inhibitors. Several small-molecule fusion inhibitors have been discovered, of which some have progressed significantly in the drug development process. BTA-9881 (Biota Holdings Ltd/MedImmune) and TMC-353121 (Johnson & Johnson) are the most advanced of this drug class. In addition, progress has been made in the development of next-generation antibodies such as motavizumab (Numax; MedImmune). This review will discuss the status and latest developments of compounds and antibodies that inhibit hRSV fusion.
Bonfanti
Jean-François
JF
Tibotec, a Division of Janssen-Cilag, Department of Medicinal Chemistry, Campus de Maigremont-BP615, Val de Reuil Cedex, France. jbonfant@its.jnj.com
Roymans
Dirk
D
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D017510:Protein Folding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy*; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors*
C528854:2-(6-((2-(3-hydroxypropyl)-5-methylphenylamino)methyl)-2-(3-morpholin-4-ylpropylamino)benzoimidazol-1-ylmethyl)-6-methylpyridin-3-ol; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D001562:Benzimidazoles; D011725:Pyridines; D054852:Small Molecule Libraries; D014760:Viral Fusion Proteins; C506968:motavizumab