Preclinical development of a potent D-peptide RSV inhibitor

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PROJECT SUMMARY Respiratory syncytial virus (RSV) is the major cause of severe lower respiratory tract infections in children and infants, affecting an estimated 64 million people and causing up to 250,000 deaths worldwide per year (WHO). In the US, ~60,000 young children and ~175,000 adults are hospitalized annually due to RSV infection. High-risk adults (the elderly and patients with chronic heart or lung disease) experience the highest RSV-attributed mortality in the US (~14,000 deaths/year), commensurate with the mortality rates of seasonal influenza. RSV costs the US healthcare system billions of dollars annually. No vaccines or safe and effective therapeutics for RSV are available, although several products are in clinical trials. Currently, RSV treatment is mostly limited to supportive care, however, for the most acute cases in children, ribavirin, a broad-range antiviral with questionable RSV efficacy and significant safety issues, can be used. Use of Synagis (palivizumab), a monoclonal antibody that inhibits RSV infection in the lower respiratory tract, is limited to the highest-risk children. Furthermore, Synagis is very expensive ($8,000 – $16,000 for a standard course of therapy for a premature infant), and it only reduces RSV-related hospitalizations by 55%. There is an urgent need for new and more cost-effective anti-RSV prophylactics and therapies that can be applied to both children and adults. During Phase I of this award, Navigen employed an innovative strategy to identify a novel, protease- resistant D-peptide drug lead, CR32T, which targets the RSV entry machinery. Our drug discovery platform employs an enantiomeric screening technology (mirror-image phage display) coupled with protein design, to identify D-peptides that bind to a conserved and functionally critical site on the virus's F (fusion) protein. CR32T binds F with pM affinity and prevents it from completing a conformational change required for RSV to enter permissive cells. As such, it is a potent inhibitor of RSV in vitro. We have successfully validated this platform technology by identifying promising inhibitors for several viruses that share a conserved entry mechanism. Our analogous anti-HIV D-peptide, CPT31, inhibits all major circulating HIV-1 strains, possesses an extremely high barrier to resistance, and has minimal immunogenicity. CPT31 has demonstrated great potential in preclinical testing, including initial safety and efficacy studies in rodents and non-human primates. Our experience with CPT31 will facilitate rapid advancement of CR32T. In this three-year Phase II application, we will determine the breadth of CR32T against multiple primary RSV isolates (A and B strains), determine its potency in a gold standard animal model of RSV infection using both preventative and therapeutic dosing regimens, and complete IND-enabling studies. Our ultimate goal is to advance this promising drug candidate to the clinic where it will have a significant worldwide impact as a safe and effective preventative and therapeutic for RSV infection in children and adults.