Molecular Similarity Relating to a Peptide Sequence Common toAngiotensin II (ANGII) and SARS-Cov2 S-Protein

Abstract

The affinity of SARS-CoV2 (Cv19) envelope proteins for angiotensin-converting enzyme 2 (ACE2) facilitates infection of human cells [1]. ACE2 cell receptors are present within several organ systems and expression in lung tissues (elevated in chronic smokers) increases significantly in airways epithelial cells infected with SARS-CoV [2]. There is 80% genome sequence identity between SARS-CoV2 and SARS-CoV1, with the latter's receptor-binding motif (RBM) for ACE2 comprising of residues 424-494 [3,4]. The amino acid sequence of the Cv19 Spike S1 receptor-binding domain (RBD) is available [5]. ACE enzymes and angiotensin peptides are essential components of the complex renin-angiotensin system (RAS) [1]. Individual susceptibility to Cv19 infection may be partially explained by natural variation within the different components of RAS [6].ACE carboxypeptidases are ectoenzymes that cleave amino acid residues from the C-terminus of proteins. Angiotensin 2 (ANGII) an octapeptide (1-8) formed from angiotensin I (1-10) by ACE is subsequently depleted of amino acids by aminopeptidases to ANGIII and smaller peptides with various effects on blood pressure, aldosterone and sodium retention [7]. The ACE2 glycoprotein, integral to cell membranes, is anchored at the hydrophobic C-terminus with an extracellular N-terminal region containing the catalytic motif of 5 amino acid residues [8,9]. Catalysis of ANG (1-7) from ANGII substrate by ACE2 is completely inhibited in vitro by high concentrations of the C-terminal dipeptide, Pro.Phe [10]. ACE2 is also susceptible to inhibition or activation by other di-and tripeptides and natural-The peptidase entity of angiotensin-converting enzyme 2 (ACE2) accommodates the receptor-binding domain of SARS-COV2 spike (S) protein initiating cell infection. Compounds binding to ACE2 or the S-protein have the potential to impair cell entry by the virus. The ACE2 substrate angiotensin II (ANGII) shares common amino acid sequences with the S-protein. This study focuses on one sequence, the N-terminal valine/arginine/aspartate peptide of ANGII. Computer modeling identifies relative molecular similarity within the tripeptide sequence and ligands for ACE2, ANGII and sigma receptor proteins with in vitro toxicity for SARS-CoV2. Molecular similarity is also evident within drug structures of several neurotransmitter classes and agents from natural sources. Application of these observations may prove useful for the further development of SARS-CoV2 antiviral drugs.