Mutation-tolerant Covid-19 drugs blocks the virus infection

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SARS-COV-2, the virus responsible for Covid-19, infects cells by binding its spike protein to angiotensin-converting enzyme 2 (ACE2) receptors. Blocking this interaction with inhibitors could prevent infection. Since these inhibitors act directly on the virus without influencing human cells, they can be safer than some existing treatments. However, mutations in the Spike protein can change its structure and reduce the effectiveness of these inhibitors.

In a significant breakthrough, a research team under the direction of Professor Yoshinori Fujiyoshi and the project assistant professor Shun Nakamura from the laboratory for cell and structure physiology, Advanced Research Initiative. The Institute for Science of Tokyo, in cooperation with the Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University, has developed an eliminative short peptide inhibition of COVID-19-Ace2 binding (Cespiace), a mutation-tolerant spike-protein inhibitor SARS-COV-2 variants remains effective. The study was published in the Procedure of the National Academy of Sciences on January 24, 2025.

“All pathogenic proteins, such as the SARS-COV-2 spike, have invariant structures that are of crucial importance for their functions, which makes it good goals for mutation-tolerant medication, as can be seen in our peptide engineering,” says Dr. Fujiyoshi.

The team aimed at the receptor portion domain (RBD), a critical region of the spike protein that are responsible for binding to ACE2 receptors. Since this region is essential for the virus function, it is less likely that it is an ideal goal. Using cryo-electron microscopy and X-ray crystallography, the researchers analyzed the RBD structure to identify targets. Based on LCB1, a mutation-sensitive RBD-binding molecule, they developed a 39-amino acid peptide, which reinforced its stability, mutation tolerance and affinity for the production of Cespiace.

Cespiace is a short peptide of natural amino acids. It forms a two-helix bundle, which with its RBD binding agency then sits in a four-helix bundle and maximizes its ability to block the spike protein from the binding to ACE2 receptors. While Cespiace primarily aims at the ACE2 binding site and ensures that mutations outside of this region do not weaken its effectiveness, it was further developed to recognize the stable backbone of the RBD, which remains unchanged even if the side chains mutate. In order to ensure a broad effectiveness between variants, the researchers created their binding surface of specific mutations, such as:

Cespiace showed a strong bond with the RBDs of the most important Sars-Cov 2 variants, with a picomolar (PM) affinity of 44 pm to 928 pm. In vivo Tests with Syrian hamsters showed that a three-day intranasal treatment against the delta variant led to a 1,000-time waste of the quantity of virus compared to untreated controls. In vitro Experiments with Calu-3 cells derived from human lungs showed a clear effectiveness against several variants (WT, Alpha, Delta and Omicron Ba.5), which blocked the viral entry into pretreated cells and prevent the reinfection of cells that are already exposed to the virus.

These results suggest that Cespiace can be used both as a prophylactic (preventive level) to block the infection, as well as as a therapeutic in the treatment of infections after exposure to the virus. In contrast to biological antibodies that can be produced complex and costly, peptides such as Cespiace are easier, cheaper and easier to produce, which enables a quick large -scale production during outbreaks. In addition, peptides are chemically stable and do not require cooling storage, which makes it easier to distribute them.

Such an approach could also be used to develop potential treatments for other viruses such as influenza or human immune deficiency virus. “Unknown infectious diseases will continue to appear. Our strategy of technical mutation-tolerant inhibitors can be applied to the development of therapeutic agents against other existing infections or future pandemics, ”says Dr. Fujiyoshi.

Reference: Nakamura S, Tanimura Y, Nomura R, et al. Structural-controlled engineering of a mutation tolerant inhibitor peptide against variable Sars-Cov-2-Spikes. PNAS. 2025; 122 (4): E2413465122. DOI: 10.1073/PNAS.2413465122

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