Targeting SARS-CoV-2 viral proteases as a therapeutic strategy to treat COVID-19

Abstract

The 21st century has witnessed three outbreaks of coronavirus (CoVs) infections caused by severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, spreads rapidly and since the discovery of the first COVID-19 infection in December 2019, has caused 1.2 million deaths worldwide and 226,777 deaths in the United States alone. The high amino acid similarity between SARS-CoV and SARS-CoV-2 viral proteins supports testing therapeutic molecules that were designed to treat SARS infections during the 2003 epidemic. In this review, we provide information on possible COVID-19 treatment strategies that act via inhibition of the two essential proteins of the virus, 3C-like protease (3CL^pro ) or papain-like protease (PL^pro ).

Keywords: 3 chymotrypsin-like cysteine protease; COVID-19; SARS coronavirus; SARS-CoV-2; coronavirus main protease; papain-like cysteine protease.

Figure 1

Classification of coronaviruses and polyproteins of SARS‐CoV. (A) Coronavirus classification. The coronavirinae subfamily divides into four genera; alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. Further division of the betacoronavirus into lineage subgroups is labeled in green. HCoV (human coronavirus), BCoV (bat coronavirus), PEDV (porcine epidemic diarrhea virus), FIPV (feline infectious peritonitis virus), SARS (severe acute respiratory syndrome), and MERS (middle east respiratory syndrome). Seven human coronaviruses are shown in red. (B) Schematics of the SARS‐CoV polyproteins with two viral protease cleavage sites. The viral proteases PL^pro and 3CL^pro cleave the immature polyproteins into 16 nonstructural proteins (labeled 1–16). Pink arrows indicate SARS‐CoV PL^pro cut sites, whereas green arrows indicate SARS‐CoV 3CL^pro cleavage sites. The structural proteins include spike (S), envelope (E), membrane (M) and nucleocapsid (N)

Figure 2

SARS‐CoV 3CLpro structure and cleavage sequences. (A) Eleven cleavage sites of SARS‐CoV and SARS‐CoV‐2 3CL^pro. Conserved residues are highlighted in yellow and highlighted in green are mismatched regions between the two 3CL^pro cleavage sites. (B) Crystal structure of the SARS‐CoV 3CL^pro (PDB; 2DUC). 3CL^pro is a functional dimer. The residues 8‐101 were colored in yellow (Domain I), 102–184 (Domain II) in pink, and 201–301 (Domain III) were colored in blue. The catalytic dyad (His41 and Cys145) is shown in green. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2

Figure 3

Cleavage sites and crystal structure of the SARS‐CoV‐ PL^pro. (A) Three cleavage sites of PL^pro protease from SARS‐CoV and SARS‐CoV‐2. Conserved residues are highlighted in yellow and highlighted in green are mismatched regions between the two PL^pro cleavage sites. (B) Crystal structure of SARS‐CoV‐2 PL^pro (PDB; 6WX4). The ubiquitin‐like domain and Zinc‐binding motif are highlighted in blue and pink, respectively. A catalytic triad is shown in the green circle and blocking loop 2 residues are in orange. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2