Cyclic β2,3-amino acids improve the serum stability of macrocyclic peptide inhibitors targeting the SARS-CoV-2 main protease

Miura, T; Malla, TR; Brewitz, L; Tumber, A; Salah, E; Lee, KJ; Terasaka, N; Owen, CD; Strain-Damerell, C; Lukacik, P; Walsh, MA; Kawamura, A; Schofield, CJ; Katoh, T; Suga, H

Journal article

Cyclic β2,3-amino acids improve the serum stability of macrocyclic peptide inhibitors targeting the SARS-CoV-2 main protease

Abstract:: Due to their constrained conformations, cyclic β2,3-amino acids (cβAA) are key building blocks that can fold peptides into compact and rigid structures, improving peptidase resistance and binding affinity to target proteins, due to their constrained conformations. Although the translation efficiency of cβAAs is generally low, our engineered tRNA, referred to as tRNAPro1E2, enabled efficient incorporation of cβAAs into peptide libraries using the flexible in vitro translation (FIT) system. Here we report on the design and application of a macrocyclic peptide library incorporating 3 kinds of cβAAs: (1R,2S)-2-aminocyclopentane carboxylic acid (β1), (1S,2S)-2-aminocyclohexane carboxylic acid (β2), and (1R,2R)-2-aminocyclopentane carboxylic acid. This library was applied to an in vitro selection against the SARS-CoV-2 main protease (Mpro). The resultant peptides, BM3 and BM7, bearing one β2 and two β1, exhibited potent inhibitory activities with IC50 values of 40 and 20 nM, respectively. BM3 and BM7 also showed remarkable serum stability with half-lives of 48 and >168 h, respectively. Notably, BM3A and BM7A, wherein the cβAAs were substituted with alanine, lost their inhibitory activities against Mpro and displayed substantially shorter serum half-lives. This observation underscores the significant contribution of cβAA to the activity and stability of peptides. Overall, our results highlight the potential of cβAA in generating potent and highly stable macrocyclic peptides with drug-like properties.

Publication status:: Published

Peer review status:: Peer reviewed

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Cite

Cite this record

APA Style

Miura, T., Malla, T. R., Brewitz, L., Tumber, A., Salah, E., Lee, K. J., Terasaka, N., Owen, C. D., Strain-Damerell, C., Lukacik, P., Walsh, M. A., Kawamura, A., Schofield, C. J., Katoh, T., & Suga, H. (2024). Cyclic β2,3-amino acids improve the serum stability of macrocyclic peptide inhibitors targeting the SARS-CoV-2 main protease. The Bulletin of the Chemical Society of Japan, 97(5), uoae018.

MLA Style

Miura, T., et al. “Cyclic β2,3-Amino Acids Improve the Serum Stability of Macrocyclic Peptide Inhibitors Targeting the SARS-CoV-2 Main Protease.” The Bulletin of the Chemical Society of Japan, vol. 97, no. 5, Chemical Society of Japan, 2024, p. uoae018.

Chicago Style

Miura, T, TR Malla, L Brewitz, A Tumber, E Salah, KJ Lee, N Terasaka, et al. 2024. “Cyclic β2,3-Amino Acids Improve the Serum Stability of Macrocyclic Peptide Inhibitors Targeting the SARS-CoV-2 Main Protease.” The Bulletin of the Chemical Society of Japan 97 (5): uoae018.
Share
Print