PEPT1, a proton-coupled oligopeptide transporter (POT) of the SLC15 family, has nutritional importance because of its intestinal absorption of small peptides from the diet and because of its reabsorption of peptide-bound amino nitrogen from glomerular filtrate in kidney. PEPT1 also has pharmacological significance in its ability to transport therapeutic agents (e.g., ?-lactam antibiotics, angiotensin-converting enzyme inhibitors, antiviral nucleoside prodrugs) and potentially toxic peptidomimetics (e.g., 5-aminolevulinic acid). However, other members of the POT family (i.e., PEPT2, PHT1 and PHT2) are expressed in the intestine and kidney, thereby confounding an accurate assessment of its role and relevance. Our laboratory has recently established a colony of PEPT1 knockout mice, a unique resource in which to validate in situ mechanistic studies with in vivo whole animal experiments. The availability of these knockout mice is particularly exciting given the recent association of aberrant PEPT1 colonic expression and inflammatory bowel disease progression. With this in mind, the long-term objectives of this "resubmission" application are to define the physiological, pharmacological, and pathological roles and relevance of PEPT1. Our working hypothesis is that PEPT1 is a critical transporter in the intestinal absorption, disposition, and dynamics of peptides and peptide-like drugs, and that it plays an important role in the pathogenesis of intestinal inflammation. To test this hypothesis, the following specific aims are proposed:
Aim 1. To determine the in situ intestinal transport properties of peptide-like drugs (and prodrugs), bacterially-derived peptides, and anti- inflammatory tripeptides;
Aim 2. To characterize the in vivo absorption and disposition of peptide-like drugs (and prodrugs), and anti-inflammatory tripeptides;
and Aim 3. To evaluate the role and relevance of PEPT1 in mediating the inflammatory response to bacterially-derived peptides and anti-inflammatory tripeptides. By combining cellular/tissue, molecular, and whole animal studies in wild-type and PEPT1 null mice, the proposed studies will greatly advance our understanding of the in vivo role, significance and vectorial transport of peptides, peptide-like drugs (and prodrugs) by PEPT1 (as opposed to other transporters and/or passive processes). Moreover, our findings will provide important new insights into the mechanisms of PEPT1- mediated intestinal inflammation and, as a result, identify a new target for therapeutic strategies against inflammatory bowel disease. Finally, the proposed studies may offer rare insight into the variability of peptide/mimetic kinetics and response in those human subjects with genetic polymorphisms.
This project will determine how a specific transporter, PEPT1, affects the absorption, disposition, and dynamics of peptides and peptide-like drugs in the body. Results from these studies will improve the safety and efficacy of drugs for bacterial and viral infections, hypertension and cancer, and facilitate the development of new drugs using a novel protein target.
|Wang, Yuqing; Sun, Dongli; Song, Feifeng et al. (2014) Expression and regulation of the proton-coupled oligopeptide transporter PhT2 by LPS in macrophages and mouse spleen. Mol Pharm 11:1880-8|
|Hu, Yongjun; Xie, Yehua; Keep, Richard F et al. (2014) Divergent developmental expression and function of the proton-coupled oligopeptide transporters PepT2 and PhT1 in regional brain slices of mouse and rat. J Neurochem 129:955-65|
|Hu, Yongjun; Xie, Yehua; Wang, Yuqing et al. (2014) Development and characterization of a novel mouse line humanized for the intestinal peptide transporter PEPT1. Mol Pharm 11:3737-46|
|Smith, David E; Clemencon, Benjamin; Hediger, Matthias A (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med 34:323-36|
|Posada, Maria M; Smith, David E (2013) In vivo absorption and disposition of cefadroxil after escalating oral doses in wild-type and PepT1 knockout mice. Pharm Res 30:2931-9|
|Huh, Yeamin; Keep, Richard F; Smith, David E (2013) Impact of lipopolysaccharide-induced inflammation on the disposition of the aminocephalosporin cefadroxil. Antimicrob Agents Chemother 57:6171-8|
|Posada, Maria M; Smith, David E (2013) Relevance of PepT1 in the intestinal permeability and oral absorption of cefadroxil. Pharm Res 30:1017-25|
|Yang, Bei; Hu, Yongjun; Smith, David E (2013) Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice. Drug Metab Dispos 41:1867-74|
|Sun, Dongli; Wang, Yuqing; Tan, Fuqing et al. (2013) Functional and molecular expression of the proton-coupled oligopeptide transporters in spleen and macrophages from mouse and human. Mol Pharm 10:1409-16|
|Wu, Shu-Pei; Smith, David E (2013) Impact of intestinal PepT1 on the kinetics and dynamics of N-formyl-methionyl-leucyl-phenylalanine, a bacterially-produced chemotactic peptide. Mol Pharm 10:677-84|
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