Modulating the fibrillization of parathyroid-hormone (PTH) peptides: azo-switches as reversible and catalytic entities

Paschold, A., et al. Biomedicines, 2022, DOI:

We here report a novel strategy to control the bioavailability of the fibrillizing parathyroid hormone (PTH)-derived peptides, where the concentration of the bioactive form is controlled by an reversible, photoswitchable peptide. We embed the azobenzene derivate 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (3,4′-AMPB) into the PTH-derived peptide PTH25–37 to generate the artificial peptide AzoPTH25–37 via solid-phase synthesis. The trans-form of AzoPTH25–37 fibrillizes similar to PTH25–37, while the cis-form of AzoPTH25–37 generates only amorphous aggregates. The approach reported here is designed to control the concentration of PTH-peptides, where the bioactive form can be catalytically controlled by an added photoswitchable peptide.

Chiral amines as initiators for ROP and chiral induction on poly(2-aminoisobutyric acid) chains

Rohmer, M.. et. al. Polymer Chemistry, 2021, 12, 6252-6262, DOI: 10.1039/D1PY01021B

2-Aminoisobutyric acid (Aib) is a prominent achiral amino acid known for its helical building properties, generating left- and right-handed helices without any preference. We here report on several short chain poly(Aib)s synthesized by ring opening polymerization (ROP) of Aib-N-carboxy-anhydrides (Aib-NCA) with structurally different chiral amines acting as both, initiator and chiral induction agent. By adding a chiral center at the C-terminus of the polymer chain we can control the direction of the screw sense, since the polymers are adopting the chirality of the initiator following the sergeant-and-soldier principle. Variation of the solvent from hexafluoroisoropanol (HFIP) to water resulted in a significant change of CD signals, featuring a surprising aggregation of the poly(amino acids) into globular aggregates in water in the range of 50 to 200 nm, which accounts for changes in chiral induction. Published with a permission of the Polymer Chemistry 2021.

Membrane Anchored Polymers Modulate Amyloid Fibrillation

Sen, N. et. al., Macromolecular Rapid Communication, 2021, 2100120,

We here report on the influence of conjugates fabricated from lipid anchors (cholesterol, diacylglycerol) and hydrophilic polymers on Aβ1-40 fibrillation, aiming to understand the impact of polymers cloud point temperature (Tcp) and its hydrophobic tails on the amyloid fibrillation. Novel lipid-polymer conjugates, consisting of poly(oligo(ethylene glycol)macrylates) and hydrophobic groups (diacylglyceryl-, cholesteryl-, octyl-, decyl-, hexadecyl-) as anchors are synthesized  via RAFT polymerization, allowing to tune the hydrophilic-hydrophobic profile of the conjugates. Hydrophobic lipid-anchors are significantly delaying fibrillation (both lag, tlag and half times, t1/2), observing similar fibrillar structures via TEM when compared to native Aβ1-40. © 2021 The Authors. Macromolecular Rapid Communications published by Wiley‐VCH GmbH

Peptide-induced RAFT polymerization via an amyloid-ß17-20 -based chain transfer agent

Kumar, S., et al. Soft Matter, 2020, 16,6964-6968, DOI: 10.1039/D0SM01169J

We here describe the synthesis of a novel  peptide/polymer-conjugate, embedding the amyloid-β (Aβ) protein core sequence Leu-Val-Phe-Phe (LVFF, Aβ17-20) via RAFT polymerization. Based on a novel chain transfer-agent, the “grafting-from” approach effectively generates the well-defined peptide-polymer conjugates with appreciably high monomer conversion rate, resulting in mechanically stiffer peptide-functional cross-linked polymeric hydrogels. Reproduced by permission of The Royal Society of Chemistry 2020.

Bifunctional Peptide-Polymer Conjugates Based Fibers via a One-Pot Tandem Disulfide Reduction Coupled to a Thio-Bromo “Click” Reaction

Kumar, S., et al. ACS Omega, 2020, 5 (30) 19020-19028

In view of the potential applications of fibers towards material sciences and biomedicine, an effective synthetic strategy is described to construct the bi-headed peptide-conjugate FFFF-PEG-FFFF (Mn,GPC= 3800 g mol-1, Ɖ = 1.10) via a one-pot, tandem–disulfide-reduction coupled to a thio-bromo“click” reaction for supramolecular self-association in solution. The conjugate was investigated via transmission electron microscopy to exploit supramolecular fibril formation and solvent dependent structuring into macroscale fibers via fibril-fibril interactions and inter-fibril cross-linking induced bundling. This synthetic approach opens the way for a simplified synthesis of PEG-containing peptide conjugates. Copyright © 2020 American Chemical Society

Tuning layered superstructures in precision polymers.

Danke, V., et al. Scientific Reports 2020, 12119,

An approach to influence and control layered superstructures by varying the methylene sequence length between two consecutive functional groups in linear precision polymers containing 2,6-diaminopyridfine (DAP) group is presented. Occurrence of different layered structures depending on crystallization conditions, methylene sequence length as well as defect type is explained by a competition of H-interactions between the DAP groups and the van der Waal forces between the hydrophobic methylene groups. Reproduced with permission. Copyright© 2020, Springer Nature.

β-Turn mimetic synthetic peptides as amyloid-β aggregation inhibitors.

Deike, S., et al. Bioorganic Chemistry 2020, 101, 104012,

Aggregation of amyloid peptides results in severe neurodegenerative diseases. We here report the preparation of beta-turn mimetic conjugates containing synthetic turn mimetic structures in the turn region of Aβ40 and Aβ16-35, replacing 2 amino acids in the turn-region G25 – K28. The structure of the turn mimic induces both, acceleration of fibrillation and the complete inhibition of fibrillation, confirming the importance of the turn region on the aggregation. Reproduced with permission. Copyright 2020© Elsevier B. V.

Thio-Bromo “Click” Reaction Derived Polymer–Peptide Conjugates for Their Self-Assembled Fibrillar Nanostructures.

Kumar, S., et al. Macromolecular Bioscience 2020,2000048,DOI:

The synthesis and self-assembly of peptide-polymer conjugates into fibrillar nanostructures are reported, based on the amyloidogenic peptide KLVFF. A strategy for rational synthesis of polymer?peptide conjugates is documented via tethering of the amyloidogenic peptide segment LVFF (Aβ17-20) and its modified derivative FFFF to the hydrophilic poly(ethylene glycol) monomethyl ether (mPEG) polymer via thio-bromo based “click” chemistry. The peptide-guided self-assembling behavior of the amphiphilic supramolecular materials is investigated exhibiting fibrillar nanostructure formation in binary aqueous solution mixture. Reproduced with permission. Copyright 2020©, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chirality Control of Screw-Sense in Aib-Polymers: Synthesis and Helicity of Amino Acid Functionalized Polymers.

Freudenberg, J., et al. ACS Macro Letters 2020, 686-692,

2-Aminoisobutyric acid (Aib) is an essential amino acid, leading to the formation of peptAibols as microbiologically active peptides and proteins. We here report on the ring-opening polymerization (ROP) of Aib-NCA (N-carboxy-anhydrides), enabling to prepare distinct Aib-polymers up to molecular weights of 1400 g/mol with precise end-group control. The attachment of chiral (D or L)-amino acids allows to systematically investigate the helical screw-sense of poly(Aib)n, resulting in chiral induction to form either left (M)- or right (P)-handed screw-senses. The approach is extended toward a switchable, chiral azo-headgroup, able to change chirality of the attached poly(Aib)n via a light-induced trigger. Reproduced with permission. Copyright 2020©, American Chemical Society.

Hybrid polymers bearing oligo-l-lysine(carboxybenzyl)s: synthesis and investigations of secondary structure.

Canalp, M., et al. RSC Advances 2020,10 (3), 1287-1295,DOI:

Hybrid polymers of peptides resembling (partially) folded protein structures are promising materials in biomedicine, especially in view of folding-interactions between different segments. In this study polymers bearing repetitive peptidic folding elements, composed of N-terminus functionalized bis-ω-ene-functional oligo-l-lysine(carboxybenzyl(Z))s (Lysn) with repeating units (n) of 3, 6, 12, 24 and 30 were successfully synthesized to study their secondary structure introduced by conformational interactions between their chains. We can demonstrate the influence of chain length of the generated polymers on the formation of secondary structures by comparing Lysnswith varying n values to the ADMET-polymers in a helicogenic solvent. Reproduced by permission of The Royal Society of Chemistry.