| Autor: |
Suryamohan K; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Diwanji D; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA., Stawiski EW; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Gupta R; MedGenome Labs Ltd., Bangalore, Karnataka, India., Miersch S; Department of Molecular Genetics, and the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada., Liu J; ModMab Therapeutics, Foster City, CA, USA., Chen C; Department of Molecular Genetics, and the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada., Jiang YP; ModMab Therapeutics, Foster City, CA, USA., Fellouse FA; ModMab Therapeutics, Accelerator for Donnelly Collaboration, University of Toronto, Toronto, ON, Canada., Sathirapongsasuti JF; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Albers PK; Wellcome Sanger Institute, Cambridge, UK., Deepak T; MedGenome Labs Ltd., Bangalore, Karnataka, India., Saberianfar R; ModMab Therapeutics, Accelerator for Donnelly Collaboration, University of Toronto, Toronto, ON, Canada., Ratan A; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Washburn G; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Mis M; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Santhosh D; ModMab Therapeutics, Foster City, CA, USA., Somasekar S; Midwestern University, Glendale, AZ, USA., Hiranjith GH; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Vargas D; Research and Development Department, MedGenome Inc, Foster City, CA, USA., Mohan S; Department of Molecular Biology, SciGenom Labs Pvt Ltd, Kochi, Kerala, India., Phalke S; Department of Molecular Biology, SciGenom Labs Pvt Ltd, Kochi, Kerala, India., Kuriakose B; AgriGenome Labs Private Ltd, Kochi, Kerala, India., Antony A; Department of Molecular Biology, SciGenom Labs Pvt Ltd, Kochi, Kerala, India., Ustav M Jr; Department of Molecular Genetics, and the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada., Schuster SC; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore., Sidhu S; Department of Molecular Genetics, and the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada., Junutula JR; ModMab Therapeutics, Foster City, CA, USA., Jura N; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA. natalia.jura@ucsf.edu.; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. natalia.jura@ucsf.edu., Seshagiri S; ModMab Therapeutics, Foster City, CA, USA. sekar@sgrf.org.; SciGenom Research Foundation, Bangalore, Karnataka, India. sekar@sgrf.org. |
| Abstrakt: |
COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10-15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus-host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2. |
