Novel chemical compounds for use as antivirals against RSV
Respiratory Syncytial Virus (RSV) is the most common cause of bronchiolitis and pneumonia among infants under one year of age. Most children will be infected with RSV prior to their second birthday, leading to 75,000-125,000 hospitalizations and medical costs exceeding $650 million annually. The virus is highly contagious and is associated with substantial morbidity and mortality. Nevertheless, severe lower respiratory tract disease may occur at any age, especially among the elderly or those with compromised cardiac, pulmonary, or immune systems. FDA-approved drugs for the acute infection are ribavirin and the prophylactic humanized monoclonal antibody, Synagis, which is limited to use in high risk pediatric patients. Due to the lack of a vaccine and the presence of toxicological limitations in existing therapies, there is substantial need for effective treatments with an improved profile.
The compounds act as antiviral inhibitors of RSV.
All stages of the RSV life cycle (attachment, entry, genomic replication, assembly, and budding) are valid targets for the actions of the probe. In addition, cellular functions that are preempted by the virus and participate in viral replication, trafficking, and release are also possible targets.
Lead compound with submicromolar potency against RSV; excellent margin of selectivity against mammalian cell cytotoxicity and ability to effectively reduce in vitro viral titer; novel chemotype with an improved profile of efficacy and safety as compared to ribavirin; intervenes at a different stage in the viral life cycle than ribavirin, and has strong potential for therapeutic use; mechanism-of-action studies have classified the probe as a post-entry inhibitor of late stage infection processes.
Compared to ribavirin, probe ML275 represents an improvement both in its therapeutic index and potential. Most of the other known compounds that have been described in the literature are entry inhibitors, prone to induce rapid emergence of viral resistance and none have progressed to reach FDA approval. Therefore, a probe which inhibits post-entry processes and has a low cytotoxicity (large therapeutic index) will address an unmet need.
The probe can be used as a tool for studying the replication cycle of RSV.