Carboxypeptidase

Internal medicine

Receptor

Enzyme

Disease

Angiotensin II

Coronavirus disease 2019 (COVID-19)

Infectious disease (medical specialty)

Blood pressure

Biology

Ectodomain

Endocrinology

Chemistry

Renin–angiotensin system

Angiotensin-converting enzyme 2

Coronavirus

Cell biology

Biochemistry

Medicine

Nature Structural & Molecular Biology

Effective intervention strategies are urgently needed to control the COVID-19 pandemic. Human angiotensin-converting enzyme 2 (ACE2) is a membrane-bound carboxypeptidase that forms a dimer and serves as the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 is also a key negative regulator of the renin–angiotensin system that modulates vascular functions. We report here the properties of a trimeric ACE2 ectodomain variant, engineered using a structure-based approach. The trimeric ACE2 variant has a binding affinity of ~60 pM for the spike protein of SARS‑CoV‑2 (compared with 77 nM for monomeric ACE2 and 12–22 nM for dimeric ACE2 constructs), and its peptidase activity and the ability to block activation of angiotensin II receptor type 1 in the renin–angiotensin system are preserved. Moreover, the engineered ACE2 potently inhibits SARS‑CoV‑2 infection in cell culture. These results suggest that engineered, trimeric ACE2 may be a promising anti-SARS-CoV-2 agent for treating COVID-19. Engineered soluble trimeric ACE2 constructs with intact enzymatic activity and high affinity to SARS-CoV-2 spike are shown to inhibit viral infection in cellular assays.

A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent