Silva, E. S. | bioRxiv Science

bioRxiv2022

Structural basis of nirmatrelvir and ensitrelvir resistance profiles against SARS-CoV-2 Main Protease naturally occurring polymorphisms

SARS-CoV-2 is the causative agent of COVID-19. Mpro is the main viral protease, with a critical role in replication and, therefore, an attractive target for antiviral drug discovery. The clinically approved drug nirmatrelvir from Pfizer, and the clinical candidate ensitrelvir from Shionogi Pharmaceuticals had so far showed great potential for treatment of viral infections. Despite the importance of new therapeutics, the broad use of antivirals is often associated with mutation selection and resistance generation. Herein, we characterized 14 naturally occurring polymorphisms that are already in circulation and are within the radius of action of these two antivirals. Nirmatrelvir retained most of its in vitro activity against most polymorphism tested, while mutants G143S and Q189K were associated with higher resistance. For ensitrelvir, higher resistance was observed for polymorphisms M49I, G143S and R188S, but not for Q189K, suggesting a distinct resistance profile difference between the two inhibitors. The crystal structures of selected polymorphism reveal the structural basis for resistance generation. Our data will assist the monitoring of potential resistant strains, support the design of combined therapy to avoid resistance, as well as assist the development of a next generation of Mpro inhibitors

biochemistry↗

bioRxiv2020

Asprosin Neutralizing Antibodies as a Treatment for Metabolic Syndrome

Recently, we discovered a new glucogenic and centrally-acting orexigenic hormone - asprosin. Asprosin is elevated in metabolic syndrome (MS) patients, and importantly, its genetic loss results in reduced appetite, leanness and robust insulin sensitivity, leading to protection from MS. Here we demonstrate that anti-asprosin monoclonal antibodies (mAbs) are a dual-effect pharmacologic therapy that targets the two key pillars of MS - over-nutrition and the blood glucose burden. Anti-asprosin mAbs from three distinct species lowered appetite and body weight, and improved blood glucose in a dose-dependent and epitope-agnostic fashion in three independent MS mouse models, with an IC50 of [~]1.5 mg/kg. In addition, mAb treatment ameliorated MS associated dyslipidemia and hepatic dysfunction. The mAbs displayed half-life of over 3 days in vivo, with equilibrium dissociation-constants in picomolar to low nanomolar range. This evidence paves the way for further development towards an investigational new drug application and subsequent human trials for treatment of MS, a defining physical ailment of our time.

physiology↗