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  • Chandramohan, ArunMSD Int, Singapore 138665, Singapore. (author)

Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • Springer Nature,2024
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-521843
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-521843URI
  • https://doi.org/10.1038/s41467-023-43346-4DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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 and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Josien, HubertMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Yuen, Tsz YingInst Sustainabil Chem Energy & Environm, Agcy Sci Technol & Res ASTAR, Singapore 138665, Singapore. (author)
  • Duggal, RuchiaMerck & Co Inc, Boston, MA 02115 USA. (author)
  • Spiegelberg, Diana,1982-Uppsala universitet,Öron-, näs- och halssjukdomar(Swepub:uu)diasp673 (author)
  • Yan, LinMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Juang, Yu-Chi AngelaMSD Int, Singapore 138665, Singapore. (author)
  • Ge, LanMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Aronica, Pietro G.Bioinformat Inst, Agcy Sci Technol & Res ASTAR, Singapore 138671, Singapore. (author)
  • Kaan, Hung Yi KristalMSD Int, Singapore 138665, Singapore. (author)
  • Lim, Yee HweeInst Sustainabil Chem Energy & Environm, Agcy Sci Technol & Res ASTAR, Singapore 138665, Singapore. (author)
  • Peier, AndreaMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Sherborne, BradMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Hochman, JeromeMerck & Co Inc, West Point, PA 19486 USA. (author)
  • Lin, SongnianMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Biswas, KaustavMerck & Co Inc, Boston, MA 02115 USA. (author)
  • Nestor, Marika,1976-Uppsala universitet,Cancerprecisionsmedicin(Swepub:uu)manes424 (author)
  • Verma, Chandra S.Bioinformat Inst, Agcy Sci Technol & Res ASTAR, Singapore 138671, Singapore. (author)
  • Lane, David P.Inst Mol & Cell Biol, Singapore 138673, Singapore. (author)
  • Sawyer, Tomi K.Merck & Co Inc, Boston, MA 02115 USA. (author)
  • Garbaccio, RobertMerck & Co Inc, Kenilworth, NJ 07033 USA. (author)
  • Henry, BrianMSD Int, Singapore 138665, Singapore. (author)
  • Kannan, SrinivasaraghavanBioinformat Inst, Agcy Sci Technol & Res ASTAR, Singapore 138671, Singapore. (author)
  • Brown, Christopher J.Inst Mol & Cell Biol, Singapore 138673, Singapore. (author)
  • Johannes, Charles W.Inst Sustainabil Chem Energy & Environm, Agcy Sci Technol & Res ASTAR, Singapore 138665, Singapore.;Inst Mol & Cell Biol, Singapore 138673, Singapore.;EPOC Sci LLC, Stoneham, MA 02180 USA. (author)
  • Partridge, Anthony W.MSD Int, Singapore 138665, Singapore.;Genentech Inc, South San Francisco, CA 94080 USA. (author)
  • MSD Int, Singapore 138665, Singapore.Merck & Co Inc, Kenilworth, NJ 07033 USA. (creator_code:org_t)

Related titles

  • In:Nature Communications: Springer Nature15:12041-1723

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