They design peptides against new variants of the COVID-19 virus

It has been possible to computationally design molecules with the capacity to neutralize in vitro the latest subvariants of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. These molecules are peptides, a very small type of protein. Having been designed using the cellular receptor for the virus itself (ACE2) as a template, these peptides, called miniACE2, could also be capable of neutralizing any other new variant of the virus that may arise in the future.

These peptides can be used in external therapy in the upper respiratory tract and in cell therapy, and have been patented.

The work is the result of collaboration between scientists from Paulino Gómez-Puertas’ group, from the Severo Ochoa Molecular Biology Center (CBM), a mixed entity of the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM), in Spain; and that of César Ramírez-Segura, from the District Institute of Science, Biotechnology and Innovation in Health (IDCBIS) in Bogotá, Colombia. The first signatory of the study is Jenny Andrea Arévalo-Romero, from IDCBIS.

The COVID-19 pandemic overwhelmed health systems in 2020-2021, triggering a global economic recession. Although vaccines have reduced the case fatality rate of SARS-CoV-2 to 0.9% by October 2024, the continued evolution of the virus, with emerging variants exhibiting widespread immune evasion, challenges the efficacy of current vaccines in the face to the future.

For the design of the aforementioned peptides, 3D computational design techniques have been used, which have united different parts of the structure of the ACE2 cellular receptor to generate a series of fragments with the capacity to bind to the SARS-CoV-2 spike. Also using computational systems, each of these peptides has been subjected to molecular dynamics simulation against the viral spike, choosing those that showed a more favorable theoretical binding energy. Once selected, these peptides have been synthesized in vitro and tested against the viral antigen of new variants in circulation. At least two of the peptides tested have given very promising results, being capable of neutralizing viral infectivity.

The main advantages of this achievement are two: on the one hand, the versatility of these peptides to be incorporated into inhalation systems in the upper respiratory tract and in chimeric antigen receptors (CAR) that would use the miniACE2 peptide sequence to act against cells infected by SARS-CoV-2. And, on the other hand, miniACE2 peptides may also have the potential to neutralize other Sarbecoviruses (the family of viruses to which SARS-CoV-2 belongs) that use ACE2 as an entry receptor. All of this underlines the potential of miniACE2 peptides as broad-spectrum pancoronaviral inhibitors.

Artist’s image of several miniACE2 peptides (in green) bound to spikes of the SARS-CoV-2 virus (in red). (Image: Paulino Gómez Puertas)

After the mass vaccination of the world population against the first variants of SARS-CoV-2, there are some possible threats that are still pending. On the one hand, the protection of people who could not be vaccinated and who, for whatever reason, cannot currently be vaccinated (for example, immunocompromised people). On the other hand, the appearance of virus variants that can escape previous vaccine protection and the appearance of new viruses from the same family for which vaccines are ineffective.

The miniACE2 peptides, with the potential to be used in respiratory therapy or incorporated into cell therapy systems, would respond to these three threats, with the ability to reduce the viral load by neutralizing infective viral particles. Furthermore, being based on the structure of the cellular receptor, these peptides could neutralize any other virus that uses the same entry route, such as new variants of SARS-CoV-2 or new viruses of the Sarbecovirus family, or even , other coronaviruses that use the same receptor.

They would thus be an early response system to be used against new epidemics in the future, as well as a solution for current cases that vaccines have not covered.

The research and development team presents the technical details of its achievement in the academic journal International Journal of Molecular Sciences, under the title “In Silico Design of miniACE2 Decoys with In Vitro Enhanced Neutralization Activity against SARS-CoV-2, Encompassing Omicron Subvariants” . And it has been published in the academic journal International Journal of Molecular Sciences. (Source: CBM/CSIC)