Development of small molecule antivirals
Lead Research Organisation:
University of Warwick
Department Name: School of Life Sciences
Abstract
The biosafety level 2 (BSL2) human respiratory syncytial virus, hRSV is one of the most common pathogenic infections of childhood, with an estimated 64 million cases and 160,000 deaths worldwide every year.2 There remains no vaccine (although with the advent of mRNA technology applied vs. SARS-CoV-2 this will change) or therapeutic, with the high-cost prophylactic palivizumab the only approved treatment.
As an archetypal negative sense RNA virus, hRSV has been an accessible target for the development of potential broad-spectrum therapies for over 50 years, with nebulised ribavirin the comparator drug. Cell biological and pull-down studies of the hRSV replication cycle enabled Easton, Gould and Marsh to uncover a host protein, DDX3X, not previously recognized as playing an essential part in HRSV replication.[1,2] We synthesized a known inhibitor of that host protein, which subsequently blocked viral growth. In common with related efforts targeting host factors in other viral infections, we hypothesize that this approach has the potential to reduce the rate of viral replication in vivo providing a window of opportunity for the host to establish a protective immune response. Furthermore, by targeting a host molecule, viral resistance to an inhibitor is less likely to develop than usual approaches against the virus itself. Synthetic chemistry work has produced ca. 50 soluble analogues displaying a range of structure-activity properties. Several ligands displayed both reduced cellular toxicity and enhanced activity, with IC50 values of about 1 - 50 M.
X-ray molecular structures of the multifunctional enzyme target are available and Marsh and co-workers have used docking and long molecular dynamics simulations with known and novel inhibitors in preliminary studies. Through a matched molecular pairs approach with MedChemica Limited, Marsh Group have two in silico libraries predicted to display enhanced solubility, reduced metabolic liability and improved activity. Marsh and co-workers have also identified additional targets including likely drug transporters for more detailed in silico work. Combining this knowledge to better understand current activity (publication 1) and select further molecules for synthesis defines Phase 1 of the project.
A small number of new and known molecules are expected to be prepared by the PhD student and an associated MChem project student 2021-22 (Phase 2). Up to 5 synthetic steps are anticipated, reflecting the increased complexity over 1 to 3 steps typically used in previous synthetic work.
Phase 3, in conjunction with Dr Phillip Gould and his research group (co-Investigator, Coventry University), the molecules will be tested against hRSV and bRSV using well-established in vitro BSL2 procedures. These data will form the basis of publication 2.
As an archetypal negative sense RNA virus, hRSV has been an accessible target for the development of potential broad-spectrum therapies for over 50 years, with nebulised ribavirin the comparator drug. Cell biological and pull-down studies of the hRSV replication cycle enabled Easton, Gould and Marsh to uncover a host protein, DDX3X, not previously recognized as playing an essential part in HRSV replication.[1,2] We synthesized a known inhibitor of that host protein, which subsequently blocked viral growth. In common with related efforts targeting host factors in other viral infections, we hypothesize that this approach has the potential to reduce the rate of viral replication in vivo providing a window of opportunity for the host to establish a protective immune response. Furthermore, by targeting a host molecule, viral resistance to an inhibitor is less likely to develop than usual approaches against the virus itself. Synthetic chemistry work has produced ca. 50 soluble analogues displaying a range of structure-activity properties. Several ligands displayed both reduced cellular toxicity and enhanced activity, with IC50 values of about 1 - 50 M.
X-ray molecular structures of the multifunctional enzyme target are available and Marsh and co-workers have used docking and long molecular dynamics simulations with known and novel inhibitors in preliminary studies. Through a matched molecular pairs approach with MedChemica Limited, Marsh Group have two in silico libraries predicted to display enhanced solubility, reduced metabolic liability and improved activity. Marsh and co-workers have also identified additional targets including likely drug transporters for more detailed in silico work. Combining this knowledge to better understand current activity (publication 1) and select further molecules for synthesis defines Phase 1 of the project.
A small number of new and known molecules are expected to be prepared by the PhD student and an associated MChem project student 2021-22 (Phase 2). Up to 5 synthetic steps are anticipated, reflecting the increased complexity over 1 to 3 steps typically used in previous synthetic work.
Phase 3, in conjunction with Dr Phillip Gould and his research group (co-Investigator, Coventry University), the molecules will be tested against hRSV and bRSV using well-established in vitro BSL2 procedures. These data will form the basis of publication 2.
