Identification and Validation of Cyclic Peptides with Mucin-Selective, Location-Specific Binding in the Gastrointestinal Tract

TL;DR

This paper identifies cyclic peptides that can selectively bind to specific mucus layers in the gastrointestinal tract, improving drug localization for oral delivery.

Contribution

The study introduces cyclic peptides as novel targeting ligands for MUC2 and MUC5AC in the GI tract to enhance drug localization.

Findings

Cyclic peptides selectively bind to MUC2 in the intestines and MUC5AC in the stomach.

Peptide incorporation increases binding and selectivity to target regions by up to 2-fold.

Experiments confirm the peptides' effectiveness in vitro, ex vivo, and in vivo.

Abstract

Oral drug delivery
is a widely preferred method of drug administration
due to its ease of use and convenience for patients. Localization
of drug release in the gastrointestinal (GI) tract is important to
treat localized diseases and maximize drug absorption. However, achieving
drug localization in the dynamic GI tract is challenging. To address
this challenge, we leveraged the geographic diversity of the GI tract
by targeting its mucus layers, which coat the epithelial surfaces.
These layers, composed of mucin glycoproteins, are synthesized with
unique chemical compositions and expressed in different regions, making
them ideal targets for drug localization. In this article, we identify
cyclic peptides that bind selectively to MUC2 (in the intestines)
and MUC5AC (in the stomach), serving as targeting ligands to these
regions of the GI tract. We demonstrate the effectiveness of these
peptides through in vitro, ex vivo, and in vivo experiments, showing that incorporating
these targeting ligands can increase binding and selectivity 2-fold
to the desired regions, thus potentially overcoming challenges with
localizing drug distribution in oral delivery. These results indicate
that cyclic peptides can be used to localize drug cargoes at certain
sites in the body compared to free drugs.

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