Pharmacologic advances in the treatment and prevention of respiratory syncytial virus

Abstract

Currently, only 2 drugs have been approved for the treatment of respiratory syncytial virus (RSV). Palivizumab is a monoclonal antibody for the prevention of RSV in high-risk children. Ribavirin is approved for treatment of severe RSV disease; however, its effectiveness in improving outcomes is questionable. During the past 40 years, many obstacles have delayed the development of safe and effective vaccines and treatment regimens. This article reviews these obstacles and presents the novel development strategies used to overcome many of them. Also discussed are promising new antiviral treatment candidates and their associated mechanism of action, the significant advances made in vaccine development, and exciting, new studies directed at improving outcomes through pharmacologic manipulation of the host response to RSV disease.

Figure 1. A cartoon showing the RSV structure and pharmacologic targets

Five of the eleven RSV proteins have been evaluated in preclinical or clinical trials as potential drug targets for anti-RSV therapy. These include the G and F glycoproteins responsible for viral attachment and fusion to host cells and the genome associated N, P, and L proteins required for RSV replication; together they are termed, the RNP complex.

Figure 2

The RSV F protein is a trimeric class I fusion protein in which each F1 monomer contains two heptad repeats, HR1 and HR2. The fusion peptides are adjacent to the HR1 segments at the amino terminus end of the F1 subunit. These peptides are responsible for fusion to target cell membranes. The HR2 segments located at the F1 carboxy terminus anchor the F glycoprotein to the viral membrane. Of the fusion inhibitors with known binding sites, all bind to the HR1 portion of the fusion glycoprotein (Table 2). Following fusion initiation, conformational changes occur in which the trimeric coiled-coil structure of three HR1 repeats is created. Three HR2 repeats collapse upon the coiled-coil structure to form a “six-helix bundle” (6HB)-complex (also referred to as a “hairpin structure” or “coiled coil heptad repeat”).[58] Modified from Drugs of the Future 2000; 25(3): 287-294. Copyright 2000 Prous Science, S.A. All rights reserved.