Re^I Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS‐CoV‐2 Main Cysteine Protease

Abstract

Since its outbreak, the severe acute respiratory syndrome—coronavirus 2 (SARS‐CoV‐2) has impacted the quality of life and cost hundreds‐of‐thousands of lives worldwide. Based on its global spread and mortality, there is an urgent need for novel treatments which can combat this disease. To date, the 3‐chymotrypsin‐like protease (3CLpro), which is also known as the main protease, is considered among the most important pharmacological targets. The vast majority of investigated 3CLpro inhibitors are organic, non‐covalent binders. Herein, the use of inorganic, coordinate covalent binders is proposed that can attenuate the activity of the protease. ReI tricarbonyl complexes were identified that demonstrate coordinate covalent enzymatic inhibition of 3CLpro. Preliminary studies indicate the selective inhibition of 3CLpro over several human proteases. This study presents the first example of metal complexes as inhibitors for the 3CLpro cysteine protease.

Potential metal-related strategies for prevention and treatment of COVID-19

“…At present, two methods are used to discover potential metal-based drugs for COVID-19: repurposing existing medications and developing new drugs [ 27 , 28 ]. These metallodrugs might directly inhibit virus replication [ 68 , 69 ], prevent viruses from entering cells [ 63 ], or inhibit the activity of critical enzymes in the process of virus replication [ 34 – 36 , 70 , 71 ]. Furthermore, the combination of antiviral drugs and metals can be more effective.…”

“…Ranitidine bismuth citrate (RBC) not only effectively inhibits NTPase and RNA helicase activities, but also shows an inhibitory effect on the ATPase (half maximal inhibitory concentration of IC 50 = 0.69 µmol·L −1 ) and DNA-unwinding (IC 50 = 0.70 µmol·L −1 ) activity of SARS-CoV-2 helicase [ 71 ]. Re(I) tricarbonyl complexes can reduce the activity of the 3-chymotrypsin-like protease (3CL pro , IC 50 = 7.5–24.1 µmol·L −1 ), which is the SARS-CoV-2 main cysteine protease [ 34 ]. Karges et al [ 34 ] synthesized and characterized a range of Re(I) tricarbonyl complexes capped by chloride and water ligands and investigated their activity in vitro.…”

“…Re(I) tricarbonyl complexes can reduce the activity of the 3-chymotrypsin-like protease (3CL pro , IC 50 = 7.5–24.1 µmol·L −1 ), which is the SARS-CoV-2 main cysteine protease [ 34 ]. Karges et al [ 34 ] synthesized and characterized a range of Re(I) tricarbonyl complexes capped by chloride and water ligands and investigated their activity in vitro. The aqua compounds show significant inhibition activity of the 3CL pro , possibly via reacting with the Cys145 active site residue (Fig.…”

Covalent Inhibition of SARS-CoV-2 RBD-ACE2 Interaction by Aptamers with Multiple Sulfur(VI) Fluoride Exchange Modifications

“…In recent years, substantial success has been achieved in developing small molecule covalent drugs as enzyme inhibitors, [15][16] including those directing towards the active sites of kinases and proteases [17][18][19] through cysteine- 20 and lysine-targeting 21 warheads. However, to target PPIs of interest, small molecules are generally inefficient in binding shallow protein surfaces or competing with PPI spanning a large binding interface at the thousand square angstrom level.…”

Covalent Bonding Aptamer with Enhanced SARS-CoV-2 RBD-ACE2 Blocking and Pseudovirus Neutralization Activities

“…Despite of the promise, no covalent RBD-ACE2 inhibitor is reported so far. Substantial success has been achieved in developing small molecule covalent drugs as enzyme inhibitors, [20][21] including those directing towards the active sites of kinases and proteases [22][23][24] through cysteine- 25 and lysine-targeting 26 warheads. However, to target PPIs of interest, small molecules are generally inefficient in binding shallow protein surfaces or competing with PPI spanning a large binding interface at the thousand square angstrom level.…”