Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00209 | DOI Listing |
EMBO J
January 2025
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates.
View Article and Find Full Text PDFEMBO J
January 2025
The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Laboratory for Protein Crystallography, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
[FeFe]-hydrogenases catalyze the reversible two-electron reduction of two protons to molecular hydrogen. Although these enzymes are among the most efficient H-converting biocatalysts in nature, their catalytic cofactor (termed H-cluster) is irreversibly destroyed upon contact with dioxygen. The [FeFe]-hydrogenase CbA5H from has a unique mechanism to protect the H-cluster from oxygen-induced degradation.
View Article and Find Full Text PDFChem Commun (Camb)
January 2025
Laboratory of Advanced Materials, Aqueous Batteries Center, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai, 200433, China.
Zinc metal is a promising anode material for zinc-ion batteries (ZIBs), but severe side reactions and dendrite formation hinder its commercialization. In this study, starch is introduced into the ZnSO electrolyte for stabilizing the Zn anode. With abundant hydroxyl groups, starch can reconstruct the H-bond system in the electrolyte, suppressing side reactions.
View Article and Find Full Text PDFInt J Biol Macromol
January 2025
Department of Food Engineering and Technology, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), Street Cristóvão Colombo, 2265, São José do Rio Preto 15054-000, Brazil. Electronic address:
In response to the growing need to expand the knowledge base on novel, more sustainable protein sources, this study investigated the effectiveness of cowpea protein concentrate (CPC) as a natural emulsifying agent, examining the relationships between pH (3-11), oil concentration (2-10 %), and emulsion stability. pH and oil concentration significantly impacted droplet size distribution, with uniformity decreasing in the order of pH 9 > pH 11 > pH 7, which was attributed to droplet coalescence and flocculation. As evidenced by circular dichroism, alkalinity induced a slight increase in the beta-sheet content of CPC, while simultaneously reducing the alpha-helix content.
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