ACE2 Co-evolutionary Pattern Suggests Targets for Pharmaceutical Intervention in the COVID-19 Pandemic

Maya Braun; Elad Sharon; Irene Unterman; Maya Miller; Anna Mellul Shtern; Shmuel Benenson; Alexander Vainstein; Yuval Tabach

doi:10.1016/j.isci.2020.101384

ACE2 Co-evolutionary Pattern Suggests Targets for Pharmaceutical Intervention in the COVID-19 Pandemic

iScience. 2020 Aug 21;23(8):101384. doi: 10.1016/j.isci.2020.101384. Epub 2020 Jul 18.

Authors

Maya Braun¹, Elad Sharon², Irene Unterman¹, Maya Miller¹, Anna Mellul Shtern¹, Shmuel Benenson³, Alexander Vainstein⁴, Yuval Tabach⁵

Affiliations

¹ Department of Developmental Biology and Cancer Research, Institute of Medical Research - Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
² Department of Developmental Biology and Cancer Research, Institute of Medical Research - Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
³ Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁴ Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
⁵ Department of Developmental Biology and Cancer Research, Institute of Medical Research - Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel. Electronic address: [email protected].

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spillover infection in December 2019 has caused an unprecedented pandemic. SARS-CoV-2, as other coronaviruses, binds its target cells through the angiotensin-converting enzyme 2 (ACE2) receptor. Accordingly, this makes ACE2 research essential for understanding the zoonotic nature of coronaviruses and identifying novel drugs. Here we present a systematic analysis of the ACE2 conservation and co-evolution protein network across 1,671 eukaryotes, revealing an unexpected conservation pattern in specific metazoans, plants, fungi, and protists. We identified the co-evolved protein network and pinpointed a list of drugs that target this network by using data integration from different sources. Our computational analysis found widely used drugs such as nonsteroidal anti-inflammatory drugs and vasodilators. These drugs are expected to perturb the ACE2 network affecting infectivity as well as the pathophysiology of the disease.

Keywords: Classification of Proteins; Evolutionary Mechanisms; Virology.