Predicting the Animal Susceptibility and Therapeutic Drugs to SARS-CoV-2 Based on Spike Glycoprotein Combined With ACE2

Abstract

Recently, a few animals have been frequently reported to have been diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether they are SARS-CoV-2 intermediate hosts is worthy of great attention. The interaction of SARS-CoV-2 spike protein and its acceptor protein ACE2 is an important issue in determining viral host range and cross-species infection, while the binding capacity of Spike protein to ACE2 of different species is unknown. Here, we used the atomic structure model of SARS-CoV-2 and human ACE2 to assess the receptor utilization capacity of ACE2s from 10 kinds of animals. Results show that chimpanzees, domestic cats and cattles are more susceptible to infection by SARS-CoV-2. Cats in particular, such as pet cats and stray cats, interact very closely with humans, implying the necessity to carefully evaluate the risk of cats during the current COVID-19 pandemic. Furthermore, based on ACE2(cats)-SARS-CoV-2-RBD model, through high-throughput screening methods using a pool of 30,000 small molecules, eight compounds were selected for binding free energy calculations. All the eight compounds can effectively interfere with the binding of ACE2 and Spike protein, especially Nelfinavir, providing drug candidates for the treatment and prevention of SARS-CoV-2, suggesting further assessment of the anti-SARS-CoV-2 activity of these compounds in cell culture. Although we only reported the results of the simulation, and more laboratory and epidemiological investigation are required. Like cats are a risk factor, we can further detect SARS-CoV-2 according to the susceptibility of different animals, find the potential host of infection, and completely cut off the living space of the virus. Especially, cats could be a choice of animal model for screening antiviral drugs or vaccine candidates against SARS-CoV-2.

Keywords: SARS-CoV-2; angiotensin-converting enzyme 2 (ACE2); binding affinity [K(b)]; cross-species transmission; nelfinavir (NFV).

FIGURE 1

Comparison of amino acids homology of ACE2 in the helical structure and the folding between human and other organisms. (a) The helical structure of 19–83 aa. (b) The folding structure of 347–358 aa. The different amino acids are shown in yellow.

FIGURE 2

Overall structure of SARS-CoV-2 RBD bound with ACE2. (A–F) Are respectively human, dogs, chimpanzees, cattles, cats, Rhesus monkey. ACE2 is colored light coffee. SARS-CoV-2 RBD core is colored cyan. Amino acid interaction sites are also shown.

FIGURE 3

Binding model of antiviral drugs with ACE2 and Spike glycoprotein complex interface. Antiviral drug binding model with ACE2 and Spike glycoprotein complex interface. (A,C,E,G) are the binding models of ACE2 and Spike glycoprotein complexes with antiviral drugs, Olysio (cyan) and related residues (off-white), (B,D,F,H) are compound Olysio (blue). The interaction-green model is located at the interface of the Spike glycoprotein complex (between coffee and white surface). The yellow dotted line indicates the interaction distance (A). (A,C,E,G) or (B,D,F,H) are nelfinavir, saquinavir, tegobuvir, and setrobuvir, respectively.

FIGURE 4

The binding model of non-antiviral drugs with the interface of ACE2 and Spike glycoprotein complexes. Antiviral drug binding model with ACE2 and Spike glycoprotein complexes interface. (A,C,E,G) are the binding models of ACE2 and Spike glycoprotein complexes with antiviral drugs, Olysio (cyan) and related residues (off-white), (B,D,F,H) are compound Olysio (blue). The interaction-green model is located at the interface of the Spike glycoprotein complex (between coffee and white surface). The yellow dotted line indicates the interaction distance (A). (A,C,E,G) or (B,D,F,H) are dihydroergotamine, dihydroergotoxine, ergotamine, fiduxosin, respectively.