Affinity prediction for substrates of the peptide transporter PepT1

Bailey, Patrick D.; Boyd, C. A. R.; Collier, Ian D.; George, John. P.; Kellett, George L.; Meredith, David; Morgan, Keith M.; Pettecrew, Rachel; Price, Richard A.

doi:10.1039/b511996k

Cited by 24 publications

(18 citation statements)

References 27 publications

(4 reference statements)

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“…A successful example is valacyclovir (valtrex/Zelitrex; GlaxoSmithKline), an antiviral drug used in the management of herpes sim plex, in which valine was attached to the parent drug acyclovir (Zovirax; GlaxoSmithKline/Biovail), leading to a fivefold increase of the oral availability 155 . Extensive analysis of the structural requirements of the PEPT1 transporter identified numerous analogues with higher affinity than valine; this information will be valuable for improving the oral availability of glycomimetics 156 .…”

Section: Std Nmr Spectroscopymentioning

confidence: 99%

From carbohydrate leads to glycomimetic drugs

Ernst

Magnani

2009

Nat Rev Drug Discov

698

600

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Carbohydrates are the most abundant natural products. Besides their role in metabolism and as structural building blocks, they are fundamental constituents of every cell surface, where they are involved in vital cellular recognition processes. Carbohydrates are a relatively untapped source of new drugs and therefore offer exciting new therapeutic opportunities. Advances in the functional understanding of carbohydrate-protein interactions have enabled the development of a new class of small-molecule drugs, known as glycomimetics. These compounds mimic the bioactive function of carbohydrates and address the drawbacks of carbohydrate leads, namely their low activity and insufficient drug-like properties. Here, we examine examples of approved carbohydrate-derived drugs, discuss the potential of carbohydrate-binding proteins as new drug targets (focusing on the lectin families) and consider ways to overcome the challenges of developing this unique class of novel therapeutics.

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Section: Std Nmr Spectroscopymentioning

confidence: 99%

From carbohydrate leads to glycomimetic drugs

Ernst

Magnani

2009

Nat Rev Drug Discov

698

600

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“…Until the exact structural features of the substrate-binding sites of PEPT1 and PEPT2 become available, this classic approach of determining affinities followed by proof of actual membrane translocation is the only way to identify new physiological substrates, drugs and prodrugs. In the last five years, however, much progress has been made in the field of computational molecular modelling studies of substrates (Gebauer et al 2003;Biegel et al 2005Biegel et al , 2006aAndersen et al 2006;Bailey et al 2006). In several earlier molecular modelling studies, inconsistent or very limited data sets from the literature, or parameters rather than actual affinity data, were collected and used.…”

Section: Molecular Modelling Of Pept1 and Pept2 Substratesmentioning

confidence: 99%

Pharmaceutical and pharmacological importance of peptide transporters

Brandsch

Knütter

Bosse-Doenecke

2008

Journal of Pharmacy and Pharmacology

196

188

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Peptide transport is currently a prominent topic in membrane research. The transport proteins involved are under intense investigation because of their physiological importance in protein absorption and also because peptide transporters are possible vehicles for drug delivery. Moreover, in many tissues peptide carriers transduce peptidic signals across membranes that are relevant in information processing. The focus of this review is on the pharmaceutical relevance of the human peptide transporters PEPT1 and PEPT2. In addition to their physiological substrates, both carriers transport many beta-lactam antibiotics, valaciclovir and other drugs and prodrugs because of their sterical resemblance to di- and tripeptides. The primary structure, tissue distribution and substrate specificity of PEPT1 and PEPT2 have been well characterized. However, there is a dearth of knowledge on the substrate binding sites and the three-dimensional structure of these proteins. Until this pivotal information becomes available by X-ray crystallography, the development of new drug substrates relies on classical transport studies combined with molecular modelling. In more than thirty years of research, data on the interaction of well over 700 di- and tripeptides, amino acid and peptide derivatives, drugs and prodrugs with peptide transporters have been gathered. The aim of this review is to put the reports on peptide transporter-mediated drug uptake into perspective. We also review the current knowledge on pharmacogenomics and clinical relevance of human peptide transporters. Finally, the reader's attention is drawn to other known or proposed human peptide-transporting proteins.

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“…Possibly the most extensive uptake transporter studies (e.g. [266,267]) have been carried out on SLC15 [268] members (previously known as PEPT1 and PEPT2), and responsible e.g. for the intestinal uptake of penicillins [269] and cepaholsporins [270,271].…”

Section: The Importance Of Qsars (Quantitative Structure-activity Relmentioning

confidence: 99%

Control of metabolite efflux in microbial cell factories: current advances and future prospects

Kell¹

2018

Preprint

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The yield and ease of purification of biotechnological products are typically greatly enhanced if they can be secreted into the external medium. Although not universally appreciated, however, small molecule biotechnological products do not ‘float across’ the phospholipid bilayer portion of biological membranes, and thus they need transporters to assist their passage into the extramembrane and extracellular spaces. Some of these transporters may be reversible, equilibrative transporters that might more normally be used for uptake, while others may have an efflux directionality imposed on them via suitable energy coupling mechanisms. Despite the energetic costs of small molecule synthesis, natural evolution does in fact provide a number of mechanisms by which the secretion of such products can actually enhance fitness. Where available these provide useful starting points, and assaying for such activities is crucial. In particular, in a systems biology approach, we first need to identify such/suitable activities before we can seek to increase them. They may then be improved through promoter engineering, via manipulation of control elements, or by directed evolution of the transporter proteins themselves. Modern methods of synthetic biology provide enormous opportunities for all kinds of efflux transporter engineering; they are just beginning to be realised.

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Affinity prediction for substrates of the peptide transporter PepT1

Abstract: A quantitative method has been developed for determining the affinity of substrates for the peptide transporter PepT1, allowing oral availability of drugs via PepT1 to be estimated.

Cited by 24 publications

References 27 publications

From carbohydrate leads to glycomimetic drugs

From carbohydrate leads to glycomimetic drugs

Pharmaceutical and pharmacological importance of peptide transporters

Control of metabolite efflux in microbial cell factories: current advances and future prospects

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