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

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Fältnamn	Indikatorer	Metadata
000		05128naa a2200601 4500
001		oai:DiVA.org:uu-521843
003		SwePub
008		240129s2024 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5218432 URI
024	7	a https://doi.org/10.1038/s41467-023-43346-42 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Chandramohan, Arunu MSD Int, Singapore 138665, Singapore.4 aut
245	1 0	a Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
264	1	b Springer Nature,c 2024
338		a electronic2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinsk bioteknologix Medicinsk bioteknologi0 (SwePub)304012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Medical Biotechnologyx Medical Biotechnology0 (SwePub)304012 hsv//eng
700	1	a Josien, Hubertu Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Yuen, Tsz Yingu Inst Sustainabil Chem Energy & Environm, Agcy Sci Technol & Res ASTAR, Singapore 138665, Singapore.4 aut
700	1	a Duggal, Ruchiau Merck & Co Inc, Boston, MA 02115 USA.4 aut
700	1	a Spiegelberg, Diana,d 1982-u Uppsala universitet,Öron-, näs- och halssjukdomar4 aut0 (Swepub:uu)diasp673
700	1	a Yan, Linu Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Juang, Yu-Chi Angelau MSD Int, Singapore 138665, Singapore.4 aut
700	1	a Ge, Lanu Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Aronica, Pietro G.u Bioinformat Inst, Agcy Sci Technol & Res ASTAR, Singapore 138671, Singapore.4 aut
700	1	a Kaan, Hung Yi Kristalu MSD Int, Singapore 138665, Singapore.4 aut
700	1	a Lim, Yee Hweeu Inst Sustainabil Chem Energy & Environm, Agcy Sci Technol & Res ASTAR, Singapore 138665, Singapore.4 aut
700	1	a Peier, Andreau Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Sherborne, Bradu Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Hochman, Jeromeu Merck & Co Inc, West Point, PA 19486 USA.4 aut
700	1	a Lin, Songnianu Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Biswas, Kaustavu Merck & Co Inc, Boston, MA 02115 USA.4 aut
700	1	a Nestor, Marika,d 1976-u Uppsala universitet,Cancerprecisionsmedicin4 aut0 (Swepub:uu)manes424
700	1	a Verma, Chandra S.u Bioinformat Inst, Agcy Sci Technol & Res ASTAR, Singapore 138671, Singapore.4 aut
700	1	a Lane, David P.u Inst Mol & Cell Biol, Singapore 138673, Singapore.4 aut
700	1	a Sawyer, Tomi K.u Merck & Co Inc, Boston, MA 02115 USA.4 aut
700	1	a Garbaccio, Robertu Merck & Co Inc, Kenilworth, NJ 07033 USA.4 aut
700	1	a Henry, Brianu MSD Int, Singapore 138665, Singapore.4 aut
700	1	a Kannan, Srinivasaraghavanu Bioinformat Inst, Agcy Sci Technol & Res ASTAR, Singapore 138671, Singapore.4 aut
700	1	a Brown, Christopher J.u Inst Mol & Cell Biol, Singapore 138673, Singapore.4 aut
700	1	a Johannes, Charles W.u 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.4 aut
700	1	a Partridge, Anthony W.u MSD Int, Singapore 138665, Singapore.;Genentech Inc, South San Francisco, CA 94080 USA.4 aut
710	2	a MSD Int, Singapore 138665, Singapore.b Merck & Co Inc, Kenilworth, NJ 07033 USA.4 org
773	0	t Nature Communicationsd : Springer Natureg 15:1q 15:1x 2041-1723
856	4	u https://doi.org/10.1038/s41467-023-43346-4y Fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:1832324/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-521843
856	4 8	u https://doi.org/10.1038/s41467-023-43346-4

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