A Rationally Designed Synthetic Antiviral Peptide Binder Targeting the Receptor-Binding Domain of SARS-CoV-2.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, is the causative agent responsible for the spread of the COVID19 pandemic across the globe. The global impact of the COVID19 pandemic, the successful approval of vaccines for controlling the pandemic, and the further resurgence of COVID19 necessitate the exploration and validation of alternative therapeutic avenues targeting SARS-CoV-2. The initial entry and further invasion by SARS-CoV-2 require strong protein-protein interactions (PPIs) between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptors expressed on the cell surfaces of various tissues. In principle, disruption of the PPIs between the RBD of SARS-CoV-2 and the ACE2 receptor by designer peptides with optimized pharmacology appears to be an ideal choice for potentially preventing viral entry with minimal immunogenicity. In this context, the current study describes a short, synthetic designer peptide (codenamed SR16, ≤18 aa, molecular weight ≤2.5 kDa), which has a few noncoded amino acids, demonstrates a helical conformation in solution, and also engages the RBD of SARS-CoV-2 through a high-affinity interaction, as judged from a battery of biophysical studies. Further, the designer peptide demonstrates resistance to trypsin degradation, appears to be nontoxic to mammalian cells, and also does not induce hemolysis in freshly isolated human erythrocytes. In summary, SR16 appears to be an ideal peptide binder targeting the RBD of SARS-CoV-2, which has the potential for further optimization and development as an antiviral agent targeting SARS-CoV-2.

Deciphering the conformational landscape of few selected aromatic noncoded amino acids (NCAAs) for applications in rational design of peptide therapeutics.

Amino acids are the essential building blocks of both synthetic and natural peptides, which are crucial for biological functions and also important as biological probes for mapping the complex protein-protein interactions (PPIs) in both prokaryotic and eukaryotic systems. Mapping the PPIs through the chemical biology approach provides pharmacologically relevant peptides, which can have agonistic or antagonistic effects on the targeted biological systems. It is evidenced that ≥ 60 peptide-based drugs have been approved by the US-FDA so far, and the number will improve further in the foreseeable future, as ≥ 140 peptides are currently in clinical trials. However, natural peptides often require fine-tuning of their pharmacological properties by strategically replacing the αL-amino acids of the peptides with non-coded amino acids (NCAA), for which codons are absent in the genetic code for biosynthesis of proteins, prior to their applications as therapeutics. Considering the diverse repertoire of the NCAAs, the conformational space of many NCAAs is yet to be explored systematically in the context of the rational design of therapeutic peptides. The current study deciphers the conformational landscape of a few such Cα-substituted aromatic NCAAs (Ing: 2-indanyl-L-Glycine; Bpa: 4-benzoyl-L-phenylalanine; Aic: 2-aminoindane-2-carboxylic acid) both in the context of tripeptides and model synthetic peptide sequences, using alanine (Ala) and proline (Pro) as the reference. The combined data obtained from the computational and biophysical studies indicate the general success of this approach, which can be exploited further to rationally design optimized peptide sequences of unusual architecture with potent antimicrobial, antiviral, gluco-regulatory, immunomodulatory, and anti-inflammatory activities.

Binding of raloxifene to human complement fragment 5a (hC5a): a perspective on cytokine storm and COVID19.

Human C5a (hC5a), one of the pro-inflammatory glycoproteins of the complement system is known to undergo production hyperdrive in response to stress and infection. hC5a has been associated with the pathogenesis of many chronic and acute diseases, due to its proven ability in triggering the 'cytokine storm', by binding to its cognate receptor C5aR, expressed in myriad of tissues. Given the pleiotropic downstream function of hC5a, it is logical to consider the hC5a or its precursors as potential drug targets, and thus, we have been rationally pursuing the idea of neutralizing the harmful effect of excessive hC5a, by implementing the repurposing strategies for FDA-approved drugs. Indeed, the proof of principle biophysical studies published recently is encouraging, which strongly supports the potential of this strategy. Considering BSA-carprofen as a reference model system, the current study further explores the inherent conformational plasticity of hC5a and its effect in accommodating more than one drug molecule cooperatively at multiple sites. The data generated by recruiting a battery of experimental and computational biology techniques strongly suggest that hC5a can sequentially accommodate more than one raloxifene molecule with an estimated Ki ∼ 0.5 µM and Ki ∼ 3.58 µM on its surface at non-analogous sites. The study hints at exploration of polypharmacology approach, as a new avenue for discovering synergistic drug molecule pairs, or drug molecules with 'broad-range' binding affinity for targeting the different 'hot spots' on hC5a, as an alternative combination therapy for possible management of the 'cytokine storm'-related inflammatory diseases, like COVID19.Communicated by Ramaswamy H. Sarma.