Mammalian peptide transporters as targets for drug delivery

Rubio‐Aliaga, Isabel; Daniel, Hannelore

doi:10.1016/s0165-6147(02)02072-2

Cited by 228 publications

(180 citation statements)

References 46 publications

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“…Since DPP III is a cytosolic enzyme, the cellular uptake of such inhibitor could be mediated by the peptide transporters PEPT1 and/or PEPT2. These plasma membrane proteins, expressed in a variety of tissues, predominantly occurring in the brush-border membranes in the small intestine and kidney, can translocate various dipeptides, tripeptides and peptide-like drugs across the biological membrane 39 .…”

Section: Effects Of Synthesized Dipeptidyl Hydroxamic Acids On the Acmentioning

confidence: 99%

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Cvitešić¹,

Sabljić

Makarević³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human dipeptidyl peptidase III (hDPP III), a zinc-metallopeptidase of the family M49, is an activator of the Keap1-Nrf2 cytoprotective pathway involved in defense against oxidative stress. Pathophysiological roles of DPP III have not been elucidated yet, partly due to the lack of specific inhibitors. We showed that substrate analog H-Tyr-Phe-NHOH is a strong competitive inhibitor of hDPP III, while H-Tyr-Gly-NHOH expresses much weaker inhibition. To investigate the effects of amino acid substitutions in inhibitor P1 position, we synthesized three new dipeptidyl hydroxamates and examined their influence on the activity of hDPP III and DPP III from the human gut symbiont Bacteroides thetaiotaomicron. The extent of inhibition of hDPP III, but not of bacterial enzyme, was dependent on the amino acid in P1. H-Phe-Phe-NHOH is recognized as one of the strongest inhibitors of hDPP III (K i ¼ 0.028 mM), and H-Phe-Leu-NHOH discriminated between human and bacterial ortholog of the M49 family.

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Section: Effects Of Synthesized Dipeptidyl Hydroxamic Acids On the Acmentioning

confidence: 99%

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Cvitešić¹,

Sabljić

Makarević³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The statistical association data here coupled with the functional data previously published suggest that kidney disease patients with the SLC15A2*2 haplotype have lower affinity and thus less uptake of peptides and/or drugs in the reabsorption process of the kidney's proximal tubule compared with patients with the SLC15A2*1 haplotype. Indeed, PEPT2 is known to transport ACE inhibitors [62], a drug often prescribed to patients with chronic kidney disease to lower blood pressure to prevent further kidney damage. ACE inhibitors should be used with caution in patients with high potassium levels as these drugs may further increase the patient's potassium levels leading to hyperkalemia.…”

Section: Adme Phewas Identifies Potential Novel Pleiotropymentioning

confidence: 99%

Evidence for Extensive Pleiotropy Among Pharmacogenes

et al. 2016

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“…It is indeed likely that only amino acids or short peptides from digested cornified cell envelope and from digested keratin can be used by dermatophytes as nutrients for growth in vivo. Bacteria, yeasts and filamentous fungi, as well as specialized cells of plants and animals, express membrane proteins for uptake of amino acids, dipeptides and tripeptides (Payne & Smith, 1994;Becker & Naider, 1995;Hauser et al, 2001;Stacey et al, 2002;Rubio-Aliaga & Daniel, 2002). Transporters that also accept oligopeptides of four or five amino acid residues are known in yeasts and plants (Lubkowitz et al, 1997;Hauser et al, 2001;Stacey et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Aminopeptidases and dipeptidyl-peptidases secreted by the dermatophyte Trichophyton rubrum

et al. 2005

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The nature of secreted aminopeptidases in Trichophyton rubrum was investigated by using a reverse genetic approach. T. rubrum genomic and cDNA libraries were screened with Aspergillus spp. and Saccharomyces cerevisiae aminopeptidase genes as the probes. Two leucine aminopeptidases, ruLap1 and ruLap2, and two dipeptidyl-peptidases, ruDppIV and ruDppV, were characterized and compared to orthologues secreted by Aspergillus fumigatus using a recombinant protein from Pichia pastoris. RuLap1 is a 33 kDa nonglycosylated protein, while ruLap2 is a 58-65 kDa glycoprotein. The hydrolytic activity of ruLap1, ruLap2 and A. fumigatus orthologues showed various preferences for different aminoacyl-7-amido-4-methylcoumarin substrates, and various sensitivities to inhibitors and cations. ruDppIV and ruDppV showed similar activities to A. fumigatus orthologues. In addition to endopeptidases, the four aminopeptidases ruLap1, ruLap2, ruDppIV and ruDppV were produced by T. rubrum in a medium containing keratin as the sole nitrogen source. Synergism between endo-and exopeptidases is likely to be essential for dermatophyte virulence, since these fungi grow only in keratinized tissues.

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Mammalian peptide transporters as targets for drug delivery

Cited by 228 publications

References 46 publications

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Evidence for Extensive Pleiotropy Among Pharmacogenes

Aminopeptidases and dipeptidyl-peptidases secreted by the dermatophyte Trichophyton rubrum

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