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Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
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- Chandramohan, Arun (author)
- MSD Int, Singapore 138665, Singapore.
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- Josien, Hubert (author)
- Merck & Co Inc, Kenilworth, NJ 07033 USA.
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- Yuen, Tsz Ying (author)
- Inst Sustainabil Chem Energy & Environm, Agcy Sci Technol & Res ASTAR, Singapore 138665, Singapore.
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- MSD Int, Singapore 138665, Singapore Merck & Co Inc, Kenilworth, NJ 07033 USA. (creator_code:org_t)
- Springer Nature, 2024
- 2024
- English.
- In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
- Journal article (peer-reviewed)
Abstract
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- Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these ‘design rules’ to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
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- art (subject category)
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