Biology subjects

Cheng, K. F.

Publications and source records attributed to Cheng, K. F..

5 recordsLinked to original sources

bioRxiv2025

Microbiome-host interactions drive a trade-off between sleep quality and lifespan in Drosophila

Understanding the interactions between various aging processes and the resulting heterogeneity in aging is crucial for promoting healthy aging. Here, we provide evidence that heterogeneity in microbiome and host interactions contributes to diversifying aging phenotypes in sleep, gut integrity, and longevity in Drosophila. Aged flies exhibiting sleep fragmentation preserve gut integrity, accompanied by a shift in microbiota composition, particularly an increase in Acinetobacter junii. A. junii induces sleep fragmentation via its metabolite, urocanic acid, through serotonin receptor-dependent dopamine upregulation. In parallel, A. junii exploits the host response to promote its growth, leading to lifespan extension, which is recapitulated by genetically modified Escherichia coli, suggesting a trade-off between sleep quality and lifespan. Our study demonstrates a systematic mechanism underlying aging heterogeneity, suggesting interventions through bacterial supplements.

animal behavior and cognition↗

bioRxiv2025

NOVEL SMALL-MOLECULE INHIBITORS OF THE PROTEIN KINASE DYRK: POTENTIAL THERAPEUTIC CANDIDATES IN CANCER

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is crucial for normal brain development and its disruption has been linked to various cancers. DYRK1A drives glioblastoma (GBM) progression via stabilization of epidermal growth factor receptor (EGFR). Here we describe two, selective, benzothiazole-derived DYRK inhibitors, FC-2 and FC-3, obtained by structure-activity optimization of a natural product lead. Both compounds inhibit DYRK1A with nanomolar potency and display high selectivity across a kinase panel. The co-crystal structure of FC-3 with DYRK1A revealed ATP-competitive binding, with interactions at the hinge region and the DYRK-specific phenylalanine gatekeeper residue explaining target selectivity. Generation of inhibitor-resistant mutants confirmed DYRK1A as the primary cellular target. In GBM cell-models, FC-2 and FC-3 impaired neurosphere self-renewal, cell invasion, and EGFR stability, phenocopying DYRK1A loss. Both compounds crossed the blood-brain barrier and suppressed tumor growth, to prolong survival in intracranial xenografts. These findings identify FC-2 and FC-3 as selective small-molecule inhibitors of DYRK1A with potential therapeutic utility in GBM.

cancer biology↗

bioRxiv2025

Atom-level backbone engineering preserves peptide function while enhancing stability

Peptide therapeutics offer unmatched potency and selectivity but are limited by rapid proteolysis and poor pharmacokinetics. Backbone engineering provides a rational approach to enhance stability while preserving function, yet direct comparisons across strategies remain scarce. Using bradykinin as a model, we systematically evaluated four backbone modifications--D-amino acid substitution, N-methylation, -methylation, and azapeptide incorporation. Each modification produced distinct outcomes in synthesis, conformation, proteolytic stability, and receptor pharmacology. While D- and N-methyl substitutions yielded high stability, they compromised receptor binding and in vivo function. In contrast, the azapeptide analogue maintained native-like affinity and physiological activity while achieving an enhanced stability profile. These findings highlight the need to balance stability and function in peptide design and position azapeptides as an underexplored class with strong therapeutic potential. More broadly, this study establishes a framework for systematic, data-driven peptide design and optimization.

biochemistry↗

bioRxiv2025

Azapeptide-based GLP-1 receptor agonist improves glucose metabolism in a diet-induced obesity model

Peptide therapeutics are limited by rapid proteolysis and short half-lives. Azapeptides, created by replacing one or more -carbon(s) on the peptide backbone with nitrogen atom(s), offer a strategy to improve peptide stability while preserving functional efficiency, yet their clinical potential has remained underexplored. Herein, we report the design, synthesis, in vitro and in vivo evaluations of azapeptide-based glucagon-like peptide-1 receptor agonists (GLP-1RAs). Using a solid-phase synthesis platform, we generated GLP-1 analogues with aza-substitutions at protease-sensitive residues. The lead analogue, AzaA8/R34-GLP-1(AzaA8), resisted dipeptidyl peptidase-4 degradation (>24 h), maintained picomolar potency at the GLP-1 receptor (GLP-1R) signaling, and exhibited an extended plasma half-life in mice relative to unmodified controls. In lean mice, AzaA8 improved oral glucose tolerance, and in high-fat diet-induced obese mice, chronic administration reduced body weight, decreased leptin and insulin levels, and enhanced glucose handling without detectable inflammatory adverse effects. These findings demonstrate that a targeted aza-substitution yields a protease-stable, biologically active GLP-1RA with metabolic benefits, establishing azapeptides as a promising scaffold for next-generation incretin-based therapies in diabetes and obesity.

biochemistry↗

bioRxiv2025

Azapeptide Synthesis Fully Integrated into Standard Solid-Phase Peptide Synthesis (SPPS): Case Study with Azapeptide-GLP-1

Azapeptide modification, achieved by substituting backbone -carbons with nitrogen atoms to form enzyme-resistant semicarbazide bonds, can markedly enhance peptide stability and therapeutic potential. However, broad application has been constrained by two major synthetic challenges: the lack of suitable building blocks and the reduced nucleophilicity of the semicarbazide amino group, which limits post-coupling efficiency in automated solid-phase peptide synthesis (SPPS). Here, we describe a fully automated azapeptide synthesis platform that employs Fmoc-protected benzotriazole esters as bench-stable, pre-activated aza-amino acid building blocks. Microwave-assisted synthesis was integrated to accelerate aza-residue incorporation and improve coupling efficiency. This plug-and-play approach enables rapid solid-phase assembly of azapeptides, substantially reducing reaction times and improving yields. To demonstrate its utility, we synthesized azapeptide analogues of glucagon-like peptide-1 (GLP-1) with targeted substitutions at protease-sensitive sites, achieving enhanced stability as demonstrated in our recent study (bioRxiv 2025). This automated platform overcomes long-standing barriers in azapeptide chemistry, providing a scalable route for the rapid generation of stabilized peptide therapeutics. Significance StatementAzapeptides are a promising class of peptidomimetics with enhanced enzymatic stability and therapeutic potential. Yet, their synthesis has been limited by two persistent barriers: the lack of suitable, stable building blocks and the reduced coupling efficiency caused by the semicarbazide backbone. We developed a fully automated, microwave-assisted solid-phase synthesis platform that overcomes both challenges by using bench-stable benzotriazole ester aza-amino acid building blocks. This plug-and-play system enables efficient incorporation of aza-residues under standard SPPS conditions, reducing reaction times while improving yields and reproducibility. The resulting platform allows rapid generation of azapeptide libraries for biological screening and drug development, representing a major step toward scalable production of protease-resistant peptide therapeutics.

biochemistry↗