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Structure and connected hydrophobicity promote endocytic uptake of single-arginine cyclic hexapeptides: lessons from wollamide B1 analogues

Year: 2026

Type: article

Abstract: clathrin- and dynamin-dependent endocytosis, accompanied by trace macropinocytosis. Side-chain modifications that expand the largest connected hydrophobic surface area (LHSA), rather than increasing total hydrophobicity, enhance uptake. The importance of the largest hydrophobic patch mirrors our previous findings for passive diffusion of uncharged cyclic hexapeptides, despite the different endocytic uptake mechanism dictated here by the charged residue. These findings demonstrate that spatial topology, connected hydrophobicity, and charged residue configuration and location collectively contribute to endocytic uptake of single-arginine cyclic hexapeptides, providing structural clues to improve cellular internalization.

Source: RSC Medicinal Chemistry

DOI: 10.1039/d6md00745g

Authors: Liping Liu, Huy N. Hoang, Lewis Goodwin, Mahan Azad, Xinyang Zhang, Timothy A. Hill, David P. Fairlie

Institutions: The University of Queensland, ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience

Language: English

Topic: RNA Interference and Gene Delivery

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Australian Research Council, National Health and Medical Research Council

OpenAlex ID: W7224771366

FWCI:

Cites: 33

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Related to: 10