9daaf21dd38f82139c3ffd092ece46d3 pmc_34065025.pdf 3186774257d04f04550f70d263c0665c8ed8efac pmc_34065025.pdf 1367b1f546d83e6b4deece90b8c99239887e5c79f47fb45376d6438708b2a3cf pmc_34065025.pdf Title: Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability Subject: A new family of hybrid ,-peptidomimetics consisting of a repetitive unit formed by a chiral cyclobutane-containing trans–amino acid plus a N-functionalized trans–amino-l-proline joined in alternation were synthesized and evaluated as cell penetrating peptides (CPP). They lack toxicity on the human tumoral cell line HeLa, with an almost negligible cell uptake. The dodecapeptide showed a substantial microbicidal activity on Leishmania parasites at 50 M but with a modest intracellular accumulation. Their previously published ,-homologues, with a cyclobutane -amino acid, showed a well-defined secondary structure with an average inter-guanidinium distance of 8–10 Å, a higher leishmanicidal activity as well as a significant intracellular accumulation. The presence of a very rigid cyclobutane -amino acid in the peptide backbone precludes the acquisition of a defined conformation suitable for their cell uptake ability. Our results unveiled the preorganized charge-display as a relevant parameter, additional to the separation among the charged groups as previously described. The data herein reinforce the relevance of these descriptors in the design of CPPs with improved properties. Keywords: peptidomimetics; cell penetrating peptides; conformational bias; rigidity; charge-preorganization Author: Ona Illa, Jimena Ospina, José-Emilio Sánchez-Aparicio, Ximena Pulido, María Ángeles Abengozar, Nerea Gaztelumendi, Daniel Carbajo, Carme Nogués, Luis Rivas, Jean-Didier Maréchal, Miriam Royo and Rosa M. 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Linotype TrueType WinAnsi yes yes no 495 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 496 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 497 0 ABCDEE+Calibri,Bold TrueType WinAnsi yes yes no 507 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 574 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 575 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 576 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 577 0 ABCDEE+Palatino Linotype,Bold CID TrueType Identity-H yes yes yes 578 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 606 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 607 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 608 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 609 0 ABCDEE+Palatino Linotype,Bold CID TrueType Identity-H yes yes yes 610 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 644 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 645 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 646 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 647 0 Times New Roman CID TrueType Identity-H yes no yes 648 0 ABCDEE+Calibri,Bold TrueType WinAnsi yes yes no 661 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 691 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 692 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 693 0 ABCDEE+Calibri,Bold TrueType WinAnsi yes yes no 701 0 JHYTSG+CMR10 Type 1 Builtin yes yes no 723 0 OEWVVO+PazoMath-Italic Type 1 Builtin yes yes no 724 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:44:40 CEST RepresentationInformation: pmc_34065025.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:13:59 CEST Size: 5179583 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: げづびふぬぴびぜ〴ぜ〰ちのつぜ〴ぜ〰いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰こべのぴとづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぐづばぴどつづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぃべぴはぴはへどっどぴべぜ〴ぜ〰ちのつぜ〴ぜ〰ぃづぬぬふぬちひぜ〴ぜ〰さばぴちにづぜ〴ぜ〰どのぜ〴ぜ〰えづがちぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰さばぴちにづ〬ぜ〴ぜ〰きどっひはぢどっどつちぬぜ〴ぜ〰ぁっぴどぶどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉのぴひちっづぬぬふぬちひぜ〴ぜ〰がはっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐづばぴどつづびぜ〴ぜ〰はのぜ〴ぜ〰がづどびとねちのどちぜ〴ぜ〰ぐちひちびどぴづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きはぬづっふぬちひぜ〴ぜ〰きはつづぬどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: こべのぴとづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぐづばぴどつづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぃべぴはぴはへどっどぴべぜ〴ぜ〰ちのつぜ〴ぜ〰ぃづぬぬふぬちひぜ〴ぜ〰さばぴちにづぜ〴ぜ〰どのぜ〴ぜ〰えづがちぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰さばぴちにづ〬ぜ〴ぜ〰きどっひはぢどっどつちぬぜ〴ぜ〰ぁっぴどぶどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉのぴひちっづぬぬふぬちひぜ〴ぜ〰がはっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐづばぴどつづびぜ〴ぜ〰はのぜ〴ぜ〰がづどびとねちのどちぜ〴ぜ〰ぐちひちびどぴづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きはぬづっふぬちひぜ〴ぜ〰きはつづぬどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぃべぴはぴはへどっどぴべぜ〴ぜ〰ちのつぜ〴ぜ〰ぃづぬぬふぬちひぜ〴ぜ〰さばぴちにづぜ〴ぜ〰どのぜ〴ぜ〰えづがちぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰さばぴちにづ〬ぜ〴ぜ〰きどっひはぢどっどつちぬぜ〴ぜ〰ぁっぴどぶどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉのぴひちっづぬぬふぬちひぜ〴ぜ〰がはっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐづばぴどつづびぜ〴ぜ〰はのぜ〴ぜ〰がづどびとねちのどちぜ〴ぜ〰ぐちひちびどぴづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きはぬづっふぬちひぜ〴ぜ〰きはつづぬどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: さばぴちにづ〬ぜ〴ぜ〰きどっひはぢどっどつちぬぜ〴ぜ〰ぁっぴどぶどぴべ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉのぴひちっづぬぬふぬちひぜ〴ぜ〰がはっちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐづばぴどつづびぜ〴ぜ〰はのぜ〴ぜ〰がづどびとねちのどちぜ〴ぜ〰ぐちひちびどぴづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰きはぬづっふぬちひぜ〴ぜ〰きはつづぬどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: きはぬづっふぬちひぜ〴ぜ〰きはつづぬどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮ㄩ‾㸊⡜㌷㙜㌷㝜〰こべのぴとづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰〬ぜ〴ぜ〰〭ぐづばぴどつづびぜ〴ぜ〰〶ぜ〲㍜〰〱〱ぜ〴ぜ〰ちのつぜ〴ぜ〰ごぁご〴〸ぜ〲㍜〰〵〷ぜ〴ぜ〰ぐづばぴどつづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰ぐづばぴどつづぜ〴ぜ〰ぐふひどてどっちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどぺちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸱ Children: Item: Title: こべのぴとづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰〬ぜ〴ぜ〰〭ぐづばぴどつづびぜ〴ぜ〰〶ぜ〲㍜〰〱〱ぜ〴ぜ〰ちのつぜ〴ぜ〰ごぁご〴〸ぜ〲㍜〰〵〷ぜ〴ぜ〰ぐづばぴどつづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰ぐづばぴどつづぜ〴ぜ〰ぐふひどてどっちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどぺちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸱ Item: Title: ぐづばぴどつづぜ〴ぜ〰ぐふひどてどっちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどぺちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸱ Item: Title: ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどぺちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸱ Children: Item: Title: くっぴちねづひどっぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰〶ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸲ Item: Title: いづっちねづひどっぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰〷ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸳ Item: Title: いはつづっちねづひどっぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰〸ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸴ Item: Title: くっぴちねづひどっぜ〴ぜ〰ぃう〭ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰〹ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸵ Item: Title: いづっちねづひどっぜ〴ぜ〰ぃう〭ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰〱〰ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸳⸶ Item: Title: いはつづっちねづひどっぜ〴ぜ〰ぃう〭ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰〱〱ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬふぬちひぜ〴ぜ〰ざどちぢどぬどぴべ〬ぜ〴ぜ〰ぉのぴづひのちぬどぺちぴどはの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰がはっちぬどぺちぴどはのぜ〴ぜ〰ぅへばづひどねづのぴびぜ〴ぜ〰ぷどぴとぜ〴ぜ〰えづがちぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: ぃづぬぬふぬちひぜ〴ぜ〰ざどちぢどぬどぴべ〬ぜ〴ぜ〰ぉのぴづひのちぬどぺちぴどはの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰がはっちぬどぺちぴどはのぜ〴ぜ〰ぅへばづひどねづのぴびぜ〴ぜ〰ぷどぴとぜ〴ぜ〰えづがちぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Children: Item: Title: えづがちぜ〴ぜ〰ぃづぬぬびぜ〴ぜ〰ぃふぬぴふひづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸲ Item: Title: ぃづぬぬふぬちひぜ〴ぜ〰ざどちぢどぬどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸳ Item: Title: ぐづばぴどつづぜ〴ぜ〰ぉのぴづひのちぬどぺちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰ぃづぬぬふぬちひぜ〴ぜ〰ざどちぢどぬどぴべ〬ぜ〴ぜ〰ぉのぴづひのちぬどぺちぴどはの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰がはっちぬどぺちぴどはのぜ〴ぜ〰ぅへばづひどねづのぴびぜ〴ぜ〰ぷどぴとぜ〴ぜ〰がづどびとねちのどちぜ〴ぜ〰ぐちひちびどぴづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸵⸱ Item: Title: ぃづぬぬふぬちひぜ〴ぜ〰ざどちぢどぬどぴべ〬ぜ〴ぜ〰ぉのぴづひのちぬどぺちぴどはの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰がはっちぬどぺちぴどはのぜ〴ぜ〰ぅへばづひどねづのぴびぜ〴ぜ〰ぷどぴとぜ〴ぜ〰がづどびとねちのどちぜ〴ぜ〰ぐちひちびどぴづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸵⸱ Children: Item: Title: ぃづぬぬふぬちひぜ〴ぜ〰ざどちぢどぬどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸵⸲ Item: Title: 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