Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused due to new coronavirus infection with 3 716075 deaths across the world as reported by the World Health Organization (WHO). SARS-CoV-2 main protease (M pro) plays a vital role in the replication of coronavirus and thus an attractive target for the screening of inhibitors for the therapy of COVID-19. The preclinical drugs ebselen and PX-12 are potent inhibitors of SARS-CoV-2 M pro and covalently modifies the active site Cys-145 residue of M pro through selenosulfide/disulfide. In the current report, using virtual screening methods, reactive sulfur species allicin is subjecting for covalent docking at the active site of SARS-CoV-2 M pro using PX-12 as a benchmark reference compound. The results indicate that allicin induces dual S-thioallylation of Cys-145 and Cys-85/ Cys-156 residues of SARS-CoV-2 M pro. Using density functional theory (DFT), Gibbs free energy change (DG) is calculated for the putative reactions between Nacetylcysteine amide thiol and allicin/allyl sulfenic acid. The overall reaction is exergonic and allyl disulfide of Cys-145 residue of M pro is involved in a sulfur mediated hydrogen bond. The results indicate that allicin causes dual S-thioallylation of SARS-CoV-2 M pro which may be of interest for treatment and attenuation of ongoing coronavirus infection.

The tetrapeptides Li504 and Li520, differing in the modification of the 4trans-hydroxylation of proline, are novel conopeptides derived from the venom duct transcriptome of the marine cone snail Conus lividus. These predicted mature peptides are homologous to the active site motif of oxidoreductases that catalyze the oxidation, reduction, and rearrangement of disulfide bonds in peptides and proteins. The estimated reduction potential of the disulfide of Li504 and Li520 is within the range of disulfide reduction potentials of oxidoreductases, indicating that they may catalyze the oxidative folding of conotoxins. Conformational features of Li504 and Li520 include the trans configuration of the Cys1−Pro2/Hyp2 peptide bond with a type 1 turn that is similar to the active site motif of glutaredoxin that regulates the oxidation of cysteine thiols to disulfides. Li504-and Li520-assisted oxidative folding of α-conotoxin ImI confirms that Li520 improves the yield of the natively folded peptide by concomitantly decreasing the yield of the non-native disulfide isomer and thus acts as a miniature disulfide isomerase. The geometry of the Cys1−Hyp2 peptide bond of Li520 shifts between the trans and cis configurations in the disulfide form and thiol/thiolate form, which regulates the deprotonation of the N-terminal cysteine residue. Hydrogen bonding of the hydroxyl group of 4-trans-hydroxyproline with the interpeptide chain unit in the mixed disulfide form may play a vital role in shifting the geometry of the Cys1−Hyp2 peptide bond from cis to trans configuration. The Li520 conopeptide together with similar peptides derived from other species may constitute a new family of "redox-active" conopeptides that are integral components of the oxidative folding machinery of conotoxins.

Vicinal cysteine disulfides are thought to be associated with specific conformations of cysteine disulfides due to the restricted rotation of single bonds in an eightmembered cyclic disulfide loop. Conformations of vicinal cysteine disulfides are analyzed using χ 1 , χ 2 , χ 3 , χ 2 ', χ 1 ' torsion angles in the crystal structures of proteins retrieved from Protein Data Bank (PDB). 85% of vicinal disulfides have (+, −)LHStaple conformation with trans configuration of the peptide bond and 9% have (−, −) RHStaple conformation with cis configured peptide bond. Conformational analysis of dipeptide Cys-Cys vicinal disulfide by density functional theory (DFT) further supported (+, −)LHStaple, (−, −)RHStaple, and (+, +)RHStaple as the preferred conformations of vicinal disulfides. Interestingly, the rare conformations of vicinal disulfides are observed in the ligand-bound forms of proteins and have higher disulfide strain energy. Conformations of vicinal disulfides in palmitoyl protein thioesterase 1, AChBP, and α7 nicotinic receptor are changed from preferred (+, −)LHStaple to rare (+, −)AntiLHHook/(+, −)AntiRHHook/(+, +)RHStaple conformation due to binding of ligands. Surprisingly, ligands are proximal to the vicinal disulfides in protein complexes that exhibited rare conformations of vicinal disulfides. The report has identified (+, −) LHStaple/(−, −) RHStaple as the hallmark conformations of vicinal disulfides and unraveled ligand-induced transition in conformations of vicinal cysteine disulfides in proteins. K E Y W O R D S conformation, crystal structure of proteins, ligand, Protein Data Bank, vicinal cysteine disulfide | INTRODUCTIONVicinal cysteine disulfide is the smallest intramolecular disulfide loop in proteins with a cyclic eight-membered ring containing either cis (or) trans configured peptide bond. [1][2][3][4] The formation of the disulfide bond between adjacent cysteine residues in the sequence results in a vicinal disulfide which is a rare, hydrophobic, and unique structural motif in polypeptide. [5][6][7][8] The constrain imposed due to ring size may restrict free rotation of side-chain single bonds of vicinal disulfide limiting their conformational space. 4,9 The restricted rotations may enforce vicinal disulfide to accommodate specific conformations of disulfides which may serve as hallmark conformations of vicinal cysteine disulfides. Structural disulfides are associated with -LHSpiral, catalytic disulfides with +/-RHHook and allosteric disulfide with -RHStaple/-LHStaple conformation. [10][11][12] Similarly, vicinal cysteine disulfides can also be mapped with the specific conformations of Abbreviations: +/−, positive/negative torsion angle; AChBP, acetyl choline binding protein; DSE, disulfide strain energy (or) dihedral strain energy; LH/RH, left-handed/right-handed; PDB, Protein Data Bank.

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