Summary The designed “ATCUN” motif (amino-terminal copper and nickel binding site) is a replica of naturally occurring ATCUN site found in many proteins/peptides, and an attractive platform for multiple applications, which include nucleases, proteases, spectroscopic probes, imaging, and small molecule activation. ATCUN motifs are engineered at periphery by conjugation to recombinant proteins, peptides, fluorophores, or recognition domains through chemically or genetically, fulfilling the needs of various biological relevance and a wide range of practical usages. This chemistry has witnessed significant growth over the last few decades and several interesting ATCUN derivatives have been described. The redox role of the ATCUN moieties is also an important aspect to be considered. The redox potential of designed M-ATCUN derivatives is modulated by judicious choice of amino acid (including stereochemistry, charge, and position) that ultimately leads to the catalytic efficiency. In this context, a wide range of M-ATCUN derivatives have been designed purposefully for various redox- and non-redox-based applications, including spectroscopic probes, target-based catalytic metallodrugs, inhibition of amyloid-β toxicity, and telomere shortening, enzyme inactivation, biomolecules stitching or modification, next-generation antibiotic, and small molecule activation.

The complex [Ph4P]2[Cu(bdt)2] (1(red)) was synthesized by the reaction of [Ph4P]2[S2MoS2CuCl] with H2bdt (bdt = benzene-1,2-dithiolate) in basic medium. 1(red) is highly susceptible toward dioxygen, affording the one electron oxidized diamagnetic compound [Ph4P][Cu(bdt)2] (1(ox)). The interconversion between these two oxidation states can be switched by addition of O2 or base (Et4NOH = tetraethylammonium hydroxide), as demonstrated by cyclic voltammetry and UV-visible and EPR spectroscopies. Thiomolybdates, in free or complex forms with copper ions, play an important role in the stability of 1(red) during its synthesis, since in its absence, 1(ox) is isolated. Both 1(red) and 1(ox) were structurally characterized by X-ray crystallography. EPR experiments showed that 1(red) is a Cu(II)-sulfur complex and revealed strong covalency on the copper-sulfur bonds. DFT calculations confirmed the spin density delocalization over the four sulfur atoms (76%) and copper (24%) atom, suggesting that 1(red) has a "thiyl radical character". Time dependent DFT calculations identified such ligand to ligand charge transfer transitions. Accordingly, 1(red) is better described by the two isoelectronic structures [Cu(I)(bdt2, 4S(3-,)*)](2-) ↔ [Cu(II)(bdt2, 4S(4-))](2-). On thermodynamic grounds, oxidation of 1(red) (doublet state) leads to 1(ox) singlet state, [Cu(III)(bdt2, 4S(4-))](1-).

SARS-CoV-2 encoded papain-like protease (PLpro) harbors a labile Zn site (Cys 189 –X–X–Cys 192 –X n –Cys 224 –X–Cys 226 ) and a classic catalytic site (Cys 111 –His 272 –Asp 286 ), which play key roles for viral replication and hence represent promising drug targets. In this Viewpoint, both sulfur-based drugs and peptides-based inhibitors may block Cys residues in the catalytic and/or Zn site of CoV-2-PLpro, leading to dysfunction of CoV-2-PLpro and thereby halting viral replication.

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Simple Cu-thiolate chemistry was developed to demonstrate the presence of copper clusters with {Cu 4 S 6 }, {Cu 5 S 7 } and {Cu 6 S 4 } cores in relevance to copper-containing metallothioneins.

Because of the uninterrupted spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious disease (COVID-19) with substantial illness and mortality rates, there is an urgent requirement of suitable antiviral agent/therapy to control this pandemic, but not yet established. The primary cause of SARS-CoV-2 infection is the crosstalk between the SARS-CoV-2 and host surface receptor protein, human angiotensin-converting enzyme 2 (hACE2), prior to cellular entry. Hence, blocking at the initial stage of virus entry could be a promising strategy/therapy to combat the SARS-CoV-2 infection. Many drugs as SARS-CoV-2 blocker have been proposed. Among them, peptide-based antivirals are one. This Viewpoint discusses the potential antiviral role and feasibility of two classes of peptides for prevention of SARS-CoV-2 infection, where (1) a designed peptide (replication of virus binding domain of hACE2), and (2) antimicrobial peptides (AMPs; natural and first line host defense peptide), both may reduce virus load into the host cell by blocking cellular surface receptors and/or disruption of virus cell membrane at the stage of virus entry. These finding may provide a novel antiviral therapy against COVID-19, which might control the current global health crisis.

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