In the quest for a highly specific and tailored treatment strategy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recent publication available on the preprint server bioRxiv describes a repository of designed peptides that interfere with the early stages of the viral invasion process.
The ongoing pandemic of coronavirus disease 2019 (COVID19), caused by SARS-CoV-2, resulted in significant health and economic disruptions with far-reaching consequences. However, thus far, no anti-SARS-CoV-2 drug or vaccine has been approved, which means novel strategies and rapid solutions are desperately needed.
Small peptides as drugs
SARS-CoV-2 is genetically closely related to SARS-CoV responsible for the original SARS outbreak in 2002, and both viruses use the angiotensin-converting enzyme 2 (ACE2) receptor as a keyhole to infect the cells. The binding occurs via the receptor-binding domain (RBD) found on the spike protein, and utilizes transmembrane serine protease enzyme known as TMPRSS2.
SARS-CoV-2 virus binding to ACE2 receptors on a human cell, the initial stage of COVID-19 infection, 3D illustration credit: Kateryna Kon / Shutterstock
This specific interaction represents a fundamental step in SARS-CoV-2 cell infection and COVID-19 development; hence, a valid treatment strategy would be to prevent this association in the first place. But the pertinent question is, what can be used to achieve the goal?
The use of peptides to inhibit protein-protein interactions is a valid approach that gained popularity in recent years, primarily due to the inherent limitations of traditional small chemicals that target such interfaces. A shining example is FDA-approved drug enfuvirtide, which inhibits the fusion of human immunodeficiency virus (HIV) with T helper immune cells.
A similar strategy using modeled structures of the protein-peptides complexes is now used by scientists from the Universitat Pompeu Fabra and Universitat de Vic-Universitat Central de Catalunya in Spain, as well as from the Aberystwyth University in the United Kingdom.
How the interactive repository was developed
The structural basis of the virus-receptor interaction is already known. There are two relevant interactions for this complex: one is between RBD and ACE2, while the other one is between ACE2 monomers. More specifically, a dimer of ACE2 is formed with a trimer of the spike protein.
The peptides were modeled using the method known as PiPreD. This knowledge-based approach employs native elements of protein-cognate partner interactions that are subsequently included in the designed peptides. This comprehensive approach samples the complete interface and derives peptide conformations optimally suited for the specific region on the protein interface.
For SARS-CoV-2, peptides identified by this technique recapitulate stretches of residues that are observed in the native interface, but also novel and highly variegated conformations that preserve the key interactions on the interface.
Finally, the obtained data was compiled in an online public repository termed PepI-Covid19. By enabling queries using conformation, size, and predicted binding energy, the whole scientific community can browse through peptides, which is particularly useful for research groups that explore novel therapeutic agents.
"PepI-Covid19 database provides an easy and convenient access to this wealth of information to the scientific community and may provide a starting point for further refinement and redesign using alternative approaches that can yields novel peptide sequences", explain study authors.
A living database
"We believe the information included in PepI-Cov19 database is a significant and worthy asset to current efforts devoted to finding novel therapeutic agents and strategies to fight SARS-CoV-2", say study authors.
And indeed, protein sequence data of potential peptide inhibitors for experimental guidance, or structural data of peptides for further computational work, are two pivotal elements where PepI-Cov19 database can contribute significantly. Moreover, users can visualize the interactive structural model of the protein-peptide by using this database.
To stay up-to-date, this repository is envisioned as 'an alive' resource that is updated as soon as new structural information on protein complexes (concerning SARS-CoV-2 cell infection) becomes available. This will enable researchers to quickly appraise potential solutions in the ongoing quest for effective COVID-19 treatments.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.