Peptide-bile acid hybrids offer promising drug candidates due to enhanced pharmacological properties, such as improved protease resistance and oral bioavailability. However, it remains unknown whether bile acids can be incorporated into peptide chains by the ribosome to produce a peptide-bile acid hybrid macrocyclic peptide library for target-based screening. In this study, we achieved the ribosomal incorporation of lithocholic acid (LCA)-d-tyrosine into peptide chains. This led to the construction of a peptide-LCA hybrid macrocyclic peptide library, which enabled the identification of peptides TP-2C-4L3 (targeting Trop2) and EP-2C-4L5 (targeting EphA2) with strong binding affinities. Notably, LCA was found to directly participate in binding to EphA2 and confer on the peptides improved stability and resistance to proteases. Cell staining experiments confirmed the high specificity of the peptides for targeting Trop2 and EphA2. This study highlights the benefits of LCA in peptides and paves the way for discovery of stable peptide-LCA hybrid drugs.
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http://dx.doi.org/10.1021/acschembio.4c00298 | DOI Listing |
Chemistry
December 2024
Keio University, Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, 105-8512, Tokyo, JAPAN.
A new miniaturized framework for graphitic material featuring three neighboring pyridinic nitrogen atoms is disclosed. The quinoline/quinazoline hybridized pseudo trimeric macrocycle, DiQuinoline(Q)-MonoQuinazolines(Qz), Q2Qz1, was readily synthesized from the key macrocyclic amide precursor in a modular fashion. Its central cavity strongly captures a proton, and the thus-formed positively charged, highly planar architecture exhibits supramolecular complexation through 𝜋-interactions.
View Article and Find Full Text PDFACS Synth Biol
December 2024
Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen 9747 AG, The Netherlands.
Lacticin 481, a ribosomally synthesized and post-translationally modified peptide (RiPP), exhibits antimicrobial activity, for which its characteristic lanthionine and methyllanthionine ring structures are essential. The post-translational introduction of (methyl)lanthionines in lacticin 481 is catalyzed by the enzyme LctM. In addition to macrocycle formation, various other post-translational modifications can enhance and modulate the chemical and functional diversity of antimicrobial peptides.
View Article and Find Full Text PDFACS Appl Mater Interfaces
December 2024
China National Institute for Food and Drug Control, Institute of Chemical Drug Control, HuaTuo Road 29, Beijing 100050, China.
Maximizing drug cargo carrying capacity in blood circulation, controlling the fate of nanoparticles, and precisely drug release to tumor targets are the main aims of multifunctional nanomedicine-based antitumor therapy. Here we combined macrocyclic polyamine di(triazole-[12]aneN) () and chemical drug camptothecin (CPT, ) through photosensitizer 1,1-dicyano-2-phenyl-2-(4-diphenylamino) phenyl-ethylene () containing the cleavable disulfide () linkage as an all-in-one theranostic nanoprodrug, . The corresponding compound with carbon chain () linkage, , was also prepared for a comparison study.
View Article and Find Full Text PDFChemistry
November 2024
Smart Hybrid Materials (SHMs) Laboratory, Division of Physical Science and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
The mechanical actuation of smart materials has garnered considerable attention in biological and medical research due to their ability to mimic biological processes at both molecular level, such as conformational changes in individual compounds, and at the macroscopic level, where polymeric substrates respond to external stimuli. In this study, we present a polymeric composite incorporating a novel urea macrocycle as a filler, forming a soft actuator that responds to various organic solvent vapors. The underlying actuation mechanism is attributed to crystalline phase transition of urea macrocycle, driven by the host-guest interactions with diverse guest molecules.
View Article and Find Full Text PDFChem Sci
November 2024
Department of Chemistry, University of Rochester Rochester NY 14627 USA.
RNA provides the genetic blueprint for many pathogenic viruses, including SARS-CoV-2. The propensity of RNA to fold into specific tertiary structures enables the biomolecular recognition of cavities and crevices suited for the binding of drug-like molecules. Despite increasing interest in RNA as a target for chemical biology and therapeutic applications, the development of molecules that recognize RNA with high affinity and specificity represents a significant challenge.
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