Preclinical development of SARS-CoV-2 helicase and macrodomain inhibitors - Targeting unique mechanisms for COVID-19 therapy

Abstract: "Eisbach has identified and validated small molecule drugs that target disease-relevant and novel mechanisms in SARS-CoV-2. Using an allosteric HTS and in vivo platform, we identified ~300 helicase inhibitors and ~60 inhibitors targeting the ADP-ribose-binding macrodomain of ALC1/CHD1L, an oncogene. We observe high sequence/structure conservation with the SARS-CoV-2 helicase and Nsp3 X-domain macrodomain mono-ADP-ribosylhyrolase, enzymes for which we have pioneering, worldwide expertise. Since the viral helicase and one of the macrodomains of SARS-CoV-2 are essential for viral replication and to suppress the host's immune system, they represent novel, highly promising drug targets. Our AI-supported molecular docking algorithm validated a binding pocket in the helicase, in particular. The 87 cell-permeable, drug-like and cell-active inhibitors that we have profiled are predicted to be high nanomolar SARS-CoV-2 blockers, have been profiled for toxicity, physchem properties and in silico ADMET. This will enable rapid lead optimization. The objectives of our grant are to develop a pre-clinical proof-of-concept for small molecule inhibitors toward the treatment of COVID-19 and other, future CoV infections. Our rationale for validating these novel inhibitors toward helicase and macrodomain ADP-ribosyl hydrolase enzymes of SARS-CoV-2 lies in the novelty of our targets, the orthogonal approach we have taken to identify small molecule inhibitors that target the helicase outside of its canonical ATP binding pocket and the specific coronavirus functions that our drugs disrupt."; Research Type: discovery; Study population: not applicable