Molecular mechanisms to target for SARS-CoV-2 therapy

September 5, 2020 0 By FM

The viral entry into human cells is the most important step for COVID-19 to manifest as an illness. SARS-CoV-2 initiates its entry into the human cell by binding to the angiotensin-converting enzyme receptor (ACE-2) on its surface. The primary interaction between the receptor-binding domain (RBD) of the S1 subunit in the spike protein and the ACE-2 receptor is shown to be highly efficacious and needed for viral entry. The disruption of this interaction is probably the most promising method to block viral entry in the very first stage of infection. As RBD-ACE2 interaction covers a large interface between these two proteins, small molecule inhibitors might lack the efficacy needed to prevent this interaction. Therefore, a peptide that mimics the ACE-2 binding region and draws away SARS-CoV-2 may be the appropriate approach.

Towards this aim, a group of researchers at Neuome Technologies designed a 1,800 peptide library using molecular dynamics simulations. Following further evaluation of these peptides using docking, a final list of 4 peptides was arrived at. These peptides have been shown in vitro to bind to pseudoviruses made from S1 protein-coated nanoparticles. The major advantage of these peptides is that they form a specific binding with S1 protein at sub-picomolar concentrations. This is the first major proof that peptide-based molecular targeting of SARS-CoV-2 is possible. Further evaluation helped the researchers drill down to a specific peptide, Pep4/D, which has the sensitivity to femtogram level binding to the S1 protein of SARS-CoV-2. The scientists have also shown that this peptide can be used for diagnostics of COVID-19 and are developing a unique approach of peptide-based detection at femtogram levels for the virus. This may yet be the most sensitive antigen detection using peptides instead of antibodies. 

The peptide was further evaluated for preventing clots or thrombus formation in alveolar pockets. This data on the prevention of viral proteins from inducing thrombus formation can be the most important feature to provide this antiviral peptide as therapy not only to prevent viral entry but also to people who are already infected and prevent pulmonary thrombosis and reduce mortality. 

Peptides designed with important features of inhibiting the viral interaction with cells and preventing further progression of the disease are important developments for peptide-based therapeutic strategies. During pandemics such as COVID-19, therapeutic interventions are needed urgently and in this regard, peptide-based therapeutics are promising alternatives due to their high specificity and low interference with other biological pathways. 

Antimicrobial peptides (AMPs) are part of the first round response to COVID-19, along with the innate and adaptive immune responses of a host. Currently, there are approximately 5000 AMPs of which 15% have shown antiviral activity against enveloped viruses. Thus, the use of AMPs has gained considerable attention as therapeutic tools against dengue virus, Zika virus, and others. Defensins are important human AMPs present in the oral cavity, intestine and other organs. Defensins are often described as the gateways of the innate immune response. Therefore, a combinatorial approach of developing AMPs from the natural human source supplemented by synthetic peptides may be a better approach to tackle COVID-19. Finally, peptide-based therapeutics can help in addressing important functions such as inhibiting viral entry, preventing pulmonary thrombosis and working closely with human defensins to improve innate immunity.