A Stapled Peptide Inhibitor of METTL3-METTL14 for Cancer Therapy

Li, Z.; Feng, Y.; Han, H.; Jiang, X.; Chen, W.; Ma, X.; Mei, Y.; Yan, X.; Yin, P.; Yuan, D.; Zhang, D.; Shi, J.

doi:10.1101/2023.09.04.556216

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bioRxiv · 10.1101/2023.09.04.556216

A Stapled Peptide Inhibitor of METTL3-METTL14 for Cancer Therapy

Li, Z.·Feng, Y.·Han, H.·Jiang, X.·Chen, W.·Ma, X.·Mei, Y.·Yan, X.·Yin, P.·Yuan, D.·Zhang, D.·Shi, J.

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Abstract

METTL3, a primary methyltransferase catalyzing RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition, although current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of RNA m6A modification. Among candidate peptides, RM3 exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the -helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysis in vivo indicated that RSM3 induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced upon RSM3 treatment, accompanied by in-creased METTL3 degradation, and reduced global RNA methylation levels in two in vivo tumor models. This peptide inhibitor thus exploits a mechanism distinct from other competitive-binding small molecules to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation.

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Li, Z., Feng, Y., Han, H., Jiang, X., Chen, W., Ma, X., Mei, Y., Yan, X., Yin, P., Yuan, D., Zhang, D., Shi, J.. 2023-09-04. A Stapled Peptide Inhibitor of METTL3-METTL14 for Cancer Therapy. https://doi.org/10.1101/2023.09.04.556216

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