Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike‐ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics**

Abstract

Gold complexes have al ong tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effectsh ave been confirmed. Herein,w e evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targetso fs evere acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugsw ere effectivei nhibitorso ft he interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2(ACE2) host receptor and might thusi nterfere with the viral entry process. The gold metallodrugsw ere also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is ak ey enzymei nt he viral replication. Regarding PLpro from SARS-CoV-2,t he here reportedi nhibitorsa re among the very first experimentally confirmed examples with activity against this target enzyme. Importantly,t he activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to removez inc ions from the labile zinc center of the enzyme. Ta ken together,the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.

Metal Complexes as Antiviral Agents for SARS‐CoV‐2

“…Interestingly, while Au3 (IC 50 >100 μM) and Au4 (IC 50 >50 μM) did not inhibit PL pro in an enzymatic assay, the other Au complexes ( Au1 , Au2 , Au5 ) demonstrated inhibition of PL pro in the low micromolar range (IC 50 =0.96–1.44 μM). Auranofin, a clinically approved antirheumatic agent, [21] showed slightly better inhibition in the high nanomolar range (IC 50 =0.75±0.13 μM) [20] . Au(I) complexes are well known to be highly thiophilic and can form coordinate covalent adducts with thiol groups of cysteine residues.…”

ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS‐CoV‐2 Main Cysteine Protease

“…The compound disulfiram, which is approved for chronic alcohol dependence, has been reported to inhibit the PL pro protease of SARS and is currently under investigation for SARS‐CoV‐2 [6] . Recently, the use of Au complexes as potential therapeutics has been reported, including as PL pro inhibitors [7, 8] . As inhibitors of the 3CL pro protease, the approved HIV therapeutics Lopinavir and Ritonavir are being studied in Phase III clinical trials for SARS‐CoV‐2 [9] .…”

Noble Metal Organometallic Complexes Display Antiviral Activity against SARS-CoV-2

“…Salt supplementation, such as with NaCl or KCl, Alternatively, the complexes may act directly on the viral proteins of the virion. Metals such as zinc and copper are common binding partners to several viral proteins [51], and collectively affect the propagation and pathogenesis of viruses including influenza, human coronaviruses, and hepatitis B virus [19,52,53]. Given our robust virucidal results, it is possible that our complexes target the SARS-CoV-2 spike (S) protein, responsible for entry into susceptible host cells.…”