Oligopeptide transporter 1 (PepT1) plays an essential role in the oral absorption of di-and tripeptides from the digestion of ingested
protein. PepT1 has become a striking prodrug-designing target recently, since some poorly absorbed drugs can be modified as
peptidomimetic prodrugs targeting intestinal PepT1 to improve membrane permeability, and eventually oral absorption of the parent
drug. However, little and no comprehensive attempts have been made to especially focus on the recent developments of prodrugs targeting
intestinal PepT1. This article summarized biology, transport mechanism, structure-transport requirements for PepT1 and significant
advances on the PepT1-targeted prodrugs within the two decades. The article also aimed to highlight some inspirations and knowledge on
the multifunctional PepT1-targeted design, which are necessary for obtaining optimal prodrug candidates. That is the requirements of
multifunctional rational PepT1 prodrugs include enough binding affinity for PepT1, controlled or targeted release of parent drug, escapement
from P-gp mediated efflux and enhanced chemical/metabolic stability. Several types of peptidomimetic prodrugs reported recently
were discussed in detail in this review.
Keywords: Oligopeptide transporter 1, oral absorption, prodrugs, substrates structure specificity.
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