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Triple‐Helix‐Stabilizing Effects in Collagen Model Peptides

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Triple‐Helix‐Stabilizing Effects in Collagen Model Peptides Angewandte Research Articles Chemie International Edition:DOI:10.1002/anie.201914101 Protein Folding German Edition:DOI:10.1002/ange.201914101 Triple-Helix-Stabilizing Effects in Collagen Model Peptides Containing PPII-Helix-Preorganized Diproline Modules Andreas Maaßen, JanM.Gebauer,Elena Theres Abraham, Isabelle Grimm, Jçrg- Martin Neudçrfl, Ronald Kühne,Ines Neundorf,Ulrich Baumann,* and Hans- Günther Schmalz* Abstract: Collagen model peptides (CMPs) serve as tools for guarantees the structural integrity of vertebrates.[1–3] In understanding stability and function of the collagen triple helix addition, collagen interacts with numerous proteins such as and have apotential for biomedical applications.Inthe past, cell-surface receptors or matrix metalloproteinases and is interstrand cross-linking or conformational preconditioning of involved in processes such as cell adhesion, proliferation, and proline units through stereoelectronic effects have been utilized extracellular matrix regulation.[4,5] Thebiocompatibility and in the design of stabilized CMPs.Tofurther study the effects bioactivity of collagen together with advances in synthetic determining collagen triple helix stability we investigated substitutes[6,7] open the path for biomedical applications such aseries of CMPs containing synthetic diproline-mimicking as bone grafts,[8,9] wound dressings,[10,11] engineering of func- modules (ProMs), whichwere preorganized in aPPII-helix- tional tissues,[12,13] tendon repair,[14] or inhibition of disease- [4,15] type conformation by afunctionalizable intrastrand C2 bridge. related target proteins. In the context of diseases,patho- Results of CD-based denaturation studies were correlated with logical conditions are coined by structural defects and calculated (DFT) conformational preferences of the ProM impaired collagen stability (e.g., osteogenesis imperfec- units,revealing that the relative helix stability is mainly ta).[16,17] Astable structure and correct folding are therefore governed by an interplay of main-chain preorganization, of fundamental importance for molecular recognition and ring-flip preference,adaptability,and steric effects.Triple helix function of collagen. At the molecular level, collagen forms integrity was proven by crystal structure analysis and binding aright-handed triple helix consisting of three peptide strands, to HSP47. which adopt aleft-handed polyproline II (PPII) type helix conformation and are held together by interstrand hydrogen Introduction bonds.[18] Arepetitive unit of three amino acids [Xxx-Yyy- Gly]n with aconserved glycine (Gly,G)and all-trans amide Collagen is the most abundant structural protein in bonds is observed. In the first two positions (Xxx and Yyy), animals,comprising afamily of 28 known members differing proline (Pro,P)or(4R)-hydroxyproline (Hyp,O)are in their composition and supramolecular assembly.Byform- predominantly found.[1] Hyp can be introduced by prolyl-4- ing fibrils and networks,this main component of the hydroxylase-mediated functionalization of proline residues.[3] extracellular matrix resides in skin, bone,and other tissues. Another member of the machinery involved in the complex Because of its unique biomechanical properties,collagen biosynthesis of collagen is the chaperone HSP47. This essential heat shock protein transiently and exclusively binds to triple helical collagen to stabilize its conformation.[3,19] [*] A. Maaßen, I. Grimm, Dr.J.-M. Neudçrfl, Prof. Dr.H.-G. Schmalz Upon binding,anarginine–aspartate salt bridge was observed UniversityofCologne, Department of Chemistry in amodel system.[20] Greinstraße 4, 50939 Cologne (Germany) Collagen model peptides (CMPs) adhering to the E-mail:[email protected] [XxxYyyGly] motif have been used to study the interactome, Dr.J.M.Gebauer,E.Theres Abraham,Prof. Dr.I.Neundorf, n the structure,and structure–stability relationships of colla- Prof. Dr.U.Baumann [1,5] UniversityofCologne, Department of Chemistry gen. Various CMPs with different amino acid substitutions ZülpicherStraße 47a, 50674 Cologne (Germany) have been prepared using preorganization as aguiding design E-mail:[email protected] principle.[2] Generally,the folding of three peptide chains into Dr.R.Kühne atriple helix is entropically unfavorable.However,ifthe Leibniz-Institut fürMolekulare Pharmakologie (FMP) tendency of the free peptide strands to adopt aPPII-helix- Campus Berlin-Buch related conformation is increased, the entropic cost for Robert-Rçssle-Straße10, 13125 Berlin (Germany) folding is decreased (Figure 1A). Accordingly,the triple- Supportinginformation and the ORCID identification number(s) for helical state can be promoted by proper preorganization. In the author(s) of this article can be found under: this context, the structural preferences (puckering) of the https://doi.org/10.1002/anie.201914101. proline pyrrolidine rings deserve special attention (Fig- 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. ure 1B). Crystal structures of proline-rich CMPs like KGaA. This is an open access article under the terms of the Creative Commons AttributionLicense, which permits use, distribution and (PPG)10 underlined that aCg-endo conformation is found in [2,21] reproduction in any medium, provided the original work is properly the Xxx position and Cg-exo in the Yyy position. As cited. substituents influence the ring-flip preference and, accord- Angew.Chem. Int.Ed. 2020, 59,5747 –5755 2020 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 5747 Angewandte Research Articles Chemie We now reasoned that scaffolds derived from ProM1 and ProM2,respectively,would represent interesting building blocks (as Pro-Pro substitutes) for the construction of CMPs. Initially,weonly expected an entropic gain due to the (partial) preorganization of the PPII helix by intrastrand bridging.However,functionalization of the alkene unit additionally allowed the synthesis of structurally related ProMs differing in their conformational preferences,flexibil- ity,bulkiness,and hydrophilicity.Herein, we report the results of asystematic study that indeed led to an improved understanding of the factors contributing to CMP triple-helix stability—as asubtle interplay of different effects. Results and Discussion Figure 1. A) Chain preorganization of aCMP by introducing an intra- strand C2 bridge (red) between pairs of prolines and triple helix folding Synthesis of ProM-Derived Scaffolds of the chains. B) Cg endo/exo ring-flip equilibriumofproline units. [21] (PPG)10 served as astructuralbasis. We started our investigation with the gram-scale synthesis of Boc-ProM1-OtBu following previously published proce- dures.[27,29] To facilitate solid phase peptide synthesis (SPPS) ingly,also the main-chain conformation, substitution at Cg of of CMPs (see below), asample of Boc-ProM1-OtBu was the proline ring has become astrategy to improve preorga- converted into the corresponding Fmoc-protected free acid nization in CMPs.[22] (Fmoc-ProM1-OH) in aone-pot procedure by TFA-induced As an example,4R-hydroxylation in Yyy position resulted cleavage of the acid-labile Boc and tert-butyl ester groups and in increased triple-helix stability by promoting both an exo- subsequent reprotection of the N-terminus with FmocCl in ring pucker and ahigh trans/cis ratio of the preceding amide the presence of NaHCO3. [2,23] bond. Theunderlying stereoelectronic effect was also As afirst C2 linker variation (Scheme 1), Boc-ProM1- exploited using (4R)-fluoroproline.[24,25] Steric effects contrib- OtBu was subjected to Pd-catalyzed catalytic hydrogenation ute to triple-helix stability as well, for instance,inthe case of to afford Boc-H2-ProM1-OtBu as acrystalline compound, 4S-methylproline.[2,25] Aparticularly strong helix stabilization which was characterized by X-ray crystallography (Figure 3). [26] was recently achieved by covalent interstrand crosslinking. Its conversion into Fmoc-H2-ProM1-OH then proceeded However,collagen triple-helix stability still remains unpre- dictable in many cases and deserves further investigation.[2] In the course of our previous studies aiming at the development of small-molecule inhibitors of the PPII helix recognizing Ena/VASP homology 1(EVH1) domain, we developed proline-derived modules (ProMs) ProM1 and ProM2 (Figure 2).[27–30] Thedesign is based on the stereo- defined covalent connection of two adjacent proline rings by aC2 bridge to freeze the system in aPPII-helix-type conformation. Scheme 1. Synthesis of ProM1-derived building blocks. Reagents and conditions: a) TFA;then FmocCl, NaHCO3,H2O/THF, 258C, 22 h; b) H2,Pd/C, MeOH, 258C, 10 min;c)oxone ,1,1,1-trifluoroacetone, NaHCO3,MeCN, 158C, 4.5 h; d) TFA, H2O, TIPS;then FmocCl, NaHCO3,H2O/THF, 188C, 2h;e)BH3·Me2S; then H2O2,aq. NaOH, THF, 08Cto258C, 2h,70%;f)TBSOTf, NEt ,CHCl , 788C, 40 min, 3 2 2 À 55%; g) RuCl3·3H2O, CeCl3,NaIO4,EtOAc/MeCN/H2O, 08C, 10 min; Figure 2. Design of ProM1 and ProM2.A)Conformational rigidification h) NaH, MeI, DMF, 08Cto258C, 2h;i)NaH, EtI, DMF, 08Cto258C, of aPro-Pro unit by stereo-controlled introductionofanethylidene 15 h; j) TFA, H2O, TIPS;then FmocCl, NaHCO3,H2O/THF, 258C, bridge (intrastrandbridging). B) Section of an idealized PPII helix 18 h; then 2,2-dimethoxypropane, p-TsOH, acetone/CH2Cl2,258C, 6h. (white) to show the structural fit upon replacementoftwo prolines by FmocCl= fluorenylmethyloxycarbonyl chloride, TBSOTf = tert-butyldi- either ProM1 or ProM2. methylsilyltrifluoromethanesulfonate, TIPS= triisopropylsilane. 5748 www.angewandte.org 2020 The
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