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.

Rational design of antibody-like peptides for targeting the human complement fragment protein C5a.

Human complement fragment 5a (C5a) is one of the most potent glycoproteins generated downstream of C3a and C4a during late-stage activation of the complement signaling cascade. C5a recruits receptors like C5aR1 and C5aR2 and is established to play a critical role in complement-mediated inflammation. Thus, excessive C5a in the plasma due to aberrant activation of the complement contributes to the pathophysiology of several chronic inflammatory diseases. Therefore, restricting the excessive interaction of C5a with its receptors by neutralizing C5a has been one of the most effective therapeutic strategies for the management of inflammatory diseases. Indeed, antibodies targeting C5 (Eculizumab), the precursor of C5a, and C5a (Vilobelimab) have already been approved by the FDA. Still, small designer peptides that work like antibodies and can target and stop C5a from interacting with its receptors seem to be a possible therapeutic alternative to antibodies because they are smaller, cheaper to make, more specific to their target, and can get through membrane barriers. As a proof-of-principle, the current study describes the computational design and evaluation of a pair of peptides that are able to form stable high-affinity complexes with the epitope regions of C5a that are important for the recruitment of C5aR1 and C5aR2. The computational data further supports the potential of designer peptides for mimicking the function of antibodies targeting C5a. However, further experimental studies will be required to establish the structure-function relationship of the designer peptides and also to establish the hypothesis of antibody-like peptides targeting C5a.