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1. Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery

   https://doi.org/10.1039/D3BM01089A  

   Zhang, Chenzhen; Zhang, Hengli; Millán Cotto, Héctor A.; Boyer, Timothy L.; Warren, Matthew R.; Wang, Chia-Ming; Luchan, Joshua; Dhal, Pradeep K.; Carrier, Rebecca L.; Bajpayee, Ambika G. (January 2024, Biomaterials Science)

   Surface modification of milk exosomes with hydrophilic and zwitterionic peptides improves stability in the gastrointestinal tract, permeability through intestinal mucus, and uptake into epithelial cells, thereby markedly increasing the efficiency of oral administration for gene delivery. 

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2. Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles

   https://doi.org/10.1073/pnas.2007304117  

   Saha, Ishika; Dang, Eric_K; Svatunek, Dennis; Houk, Kendall_N; Harran, Patrick_G (September 2020, Proceedings of the National Academy of Sciences)

   Significance We describe computations to anticipate products of multistep reaction sequences. The work is based on experimental methods developed earlier to amalgamate synthetic scaffolding reagents with small linear peptides. Hybrid products retain molecular recognition elements in the peptide, but display that functionality as part of amphipathic macrocycles having defined conformations and improved pharmacological properties. The hypothetical scope of the chemistry is large and far outpaces the experimental format. To explore the structure space more extensively, we devised algorithms to predict outcomes of more than 2 billion processing sequences. Software was also developed to generate accurate three-dimensional structures for each product. The resultant virtual library is a resource that can be deployed broadly in search of novel ligands for protein receptors. 

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3. Capture of Phenylalanine and Phenylalanine-Terminated Peptides Using a Supramolecular Macrocycle for Surface-Enhanced Raman Scattering Detection

   https://doi.org/10.1177/0003702820937333  

   Olson, Jacob E.; Braegelman, Adam S.; Zou, Lei; Webber, Matthew J.; Camden, Jon P. (November 2020, Applied Spectroscopy)

   null (Ed.)

   The cucurbit[n]uril (CB[ n]) family of macrocycles are known to bind a variety of small molecules with high affinity. These motifs thus have promise in an ever-growing list of trace detection methods. Surface-enhanced Raman scattering (SERS) detection schemes employing CB[ n] motifs exhibit increased sensitivity due to selective concentration of the analyte at the nanoparticle surface, coupled with the ability of CB[ n] to facilitate the formation of well-defined electromagnetic hot spots. Herein, we report a CB[7] SERS assay for quantification of phenylalanine (Phe) and further demonstrate its utility for detecting peptides with an N-terminal Phe. The CB[7]–guest interaction improves the sensitivity 5–25-fold over direct detection of Phe using citrate-capped silver nanoparticle aggregates, enabling use of a portable Raman system. We further illustrate detection of insulin via binding of CB[7] to the N-terminal Phe residue on its B-chain, suggesting a general strategy for detecting Phe-terminated peptides of clinically relevant biomolecules. 

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4. Functionalization of Bacterial Cellulose with the Antimicrobial Peptide KR-12 via Chimerical Cellulose-Binding Peptides

   https://doi.org/10.3390/ijms25031462  

   van Zyl, Elizabeth M.; Coburn, Jeannine M. (January 2024, International Journal of Molecular Sciences)

   Bacterial-derived cellulose (BC) has been studied as a promising material for biomedical applications, including wound care, due to its biocompatibility, water-holding capacity, liquid/gas permeability, and handleability properties. Although BC has been studied as a dressing material for cutaneous wounds, to date, BC inherently lacks antibacterial properties. The current research utilizes bifunctional chimeric peptides containing carbohydrate binding peptides (CBP; either a short version or a long version) and an antimicrobial peptide (AMP), KR-12. The secondary structure of the chimeric peptides was evaluated and confirmed that the α-helix structure of KR-12 was retained for both chimeric peptides evaluated (Long-CBP-KR12 and Short-CBP-KR12). Chimeric peptides and their individual components were assessed for cytotoxicity, where only higher concentrations of Short-CBP and longer timepoints of Short-CBP-KR12 exposure exhibited negative effects on metabolic activity, which was attributed to solubility issues. All KR-12-containing peptides exhibited antibacterial activity in solution against Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). The lipopolysaccharide (LPS) binding capability of the peptides was evaluated and the Short-CBP-KR12 peptide exhibited enhanced LPS-binding capabilities compared to KR-12 alone. Both chimeric peptides were able to bind to BC and were observed to be retained on the surface over a 7-day period. All functionalized materials exhibited no adverse effects on the metabolic activity of both normal human dermal fibroblasts (NHDFs) and human epidermal keratinocyte (HaCaT) epithelial cells. Additionally, the BC tethered chimeric peptides exhibited antibacterial activity against E. coli. Overall, this research outlines the design and evaluation of chimeric CBP-KR12 peptides for developing antimicrobial BC membranes with potential applications in wound care. 

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5. Mismatched covalent and noncovalent templating leads to large coiled coil-templated macrocycles

   https://doi.org/10.1039/D3SC00231D  

   Stingley, Kyla J.; Carpenter, Benjamin A.; Kean, Kelsey M.; Waters, Marcey L. (May 2023, Chemical Science)

   Herein we describe the use of dynamic combinatorial chemistry to self-assemble complex coiled coil motifs. We amide-coupled a series of peptides designed to form homodimeric coiled coils with 3,5-dithiobenzoic acid (B) at the N-terminus and then allowed each B-peptide to undergo disulfide exchange. In the absence of peptide, monomer B forms cyclic trimers and tetramers, and thus we expected that addition of the peptide to monomer B would shift the equilibrium towards the tetramer to maximize coiled coil formation. Unexpectedly, we found that internal templation of the B-peptide through coiled coil formation shifts the equilibrium towards larger macrocycles up to 13 B-peptide subunits, with a preference for 4, 7, and 10-membered macrocycles. These macrocyclic assemblies display greater helicity and thermal stability relative to intermolecular coiled coil homodimer controls. The preference for large macrocycles is driven by the strength of the coiled coil, as increasing the coiled coil affinity increases the fraction of larger macrocycles. This system represents a new approach towards the development of complex peptide and protein assemblies. 

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