Assembly Modulation: An Emergent Drug Discovery Strategy Revealed by Viruses and Applicable Across Therapeutic Areas

Evolution through natural selection is the most powerful force we know of in biology. Perhaps its most adept practitioners are viruses, particularly retroviruses. Approximately 10% of the human genome, and numerous physiological innovations (from cognition to the placenta), are likely due to ancient retroviral infections, a testimony to how they have shaped who we are. A set of methods have been developed which effectively turn viruses into “trufflehounds” to reveal the high value molecular targets that viruses utilized to redirect a host cell’s protein machinery to depart from homeostasis (the balance that characterizes good health). We leveraged viral discovery of functional targets in phenotypic drug screens for antiviral activity, enabling the discovery of functional compounds with which we have made several notable observations. First, we find that the same targets in our biology that viruses have exploited, are the ones that break in non-viral diseases, including cancer and neurodegeneration. Second, it appears that these drugs bind to allosteric sites, the natural control panels by which enzymes evolved to be regulated, but which have proven fiendishly difficult to identify directly by human tools. Third, these compounds appear to have remarkable properties (e.g. barrier to viral resistance) and may enable currently impossible clinical therapeutic strategies. Compounds with these features, active against various viral and non-viral disorders, are being advanced. Along the way they are revealing new features of biology. Two papers published last year in Open Biology, are the focus of this webinar. The first on a small molecule active against all of the major viral families causing human respiratory tract disease, including influenza, RSV and SARS-CoV-2, and the second paper on a small molecule active against over 80 different tumor cell lines, including all cancers in the National Cancer Institute’s 60 cancer screen. Both have been validated in animals and advanced analogs from each chemotype are poised to advance to human clinical trials. Each bind to novel, unconventional targets: different transient, energy-dependent multi-protein complexes composed of miniscule subsets of their component proteins in the cell. These features make them hard to detect by genomic or conventional proteomic methods. This webinar will review the data in these two publications and connect them to broader questions, biochemical and clinical, with regards to human health and disease.