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The passive membrane permeation of small-molecule drugs and relatively small hydrophobic peptides is relatively well understood. In contrast, how long polar peptides can directly pass through a membrane has remained a mystery. This process can be achieved with transcellular permeation enhancers, contributing significantly to the oral transcellular absorption of important peptide drugs like semaglutide — the active component in Ozempic, which is used as Rybelsus in a successful oral formulation. Here we now provide, for the first time, a detailed, plausible molecular mechanism of how such a polar peptide can realistically pass through a membrane paired with the permeation enhancer salcaprozate sodium (SNAC). We provide not only simulation results, obtained with scalable continuous constant pH molecular dynamics (CpHMD) simulations, but also experimental evidence (NMR, DOSY, and DLS) to support this unique passive permeation mechanism. Our computational and experimental evidence points toward the formation of permeation-enhancer-filled, fluid membrane defects, in which the polar peptide can be submerged in a process analogous to sinking in quicksand.
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Peptide‐Modulated pH Rhythms
Abstract Many drugs adjust and/or control the spatiotemporal dynamics of periodic processes such as heartbeat, neuronal signaling and metabolism, often by interacting with proteins or oligopeptides. Here we use a quasi‐biocompatible, non‐equilibrium pH oscillatory system as a biomimetic biological clock to study the effect of pH‐responsive peptides on rhythm dynamics. The added peptides generate feedback that can lengthen or shorten the oscillatory period during which the peptides alternate between random coil and coiled‐coil conformations. This modulation of a chemical clock supports the notion that short peptide reagents may have utility as drugs to regulate human body clocks.
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- Award ID(s):
- 1856484
- PAR ID:
- 10369819
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemPhysChem
- Volume:
- 23
- Issue:
- 16
- ISSN:
- 1439-4235
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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