Activity of a peptidyl prodrug, alafosfalin, against anaerobic bacteria

Grappel, Sarah F.; Giovenella, Albert J.; Nisbet, Louis J.

doi:10.1128/aac.27.6.961

Cited by 11 publications

(4 citation statements)

References 8 publications

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“…It does not necessarily mean that the phosphonodipeptide is actually transported into the cells. Interaction with PEPT1 and PEPT2, the fact that bacterial permeases take up alafosfalin [11][12][13][14] and the known oral availability of alafosfalin, can only be regarded Table 1. Effect of alafosfalin on the transepithelial flux and the intracellular accumulation of [ 14 C]Gly-Sar at Caco-2 and SKPT cell monolayers.…”

Section: Transport Of Alafosfalin -Short-circuit Current Measurementsmentioning

confidence: 99%

“…It does not necessarily mean that the phosphonodipeptide is actually transported into the cells. Interaction with PEPT1 and PEPT2, the fact that bacterial permeases take up alafosfalin [11–14] and the known oral availability of alafosfalin, can only be regarded as circumstantial evidence for actual transport. Therefore, we exploited the electrogenic nature of H + /peptide symporters in an Ussing‐type of experiment to obtain more direct evidence.…”

Section: Transport Of Alafosfalin – Short‐circuit Current Measurementsmentioning

confidence: 99%

“…Several authors have studied bacterial uptake and intracellular metabolism of phosphonopeptides. They have demonstrated the uptake of alafosfalin into bacteria by peptide permeases located in the cytoplasmic membrane [1,[11][12][13][14]. However, there are no detailed studies regarding the specific uptake mechanism at mammalian cells for phosphonodipeptides such as alafosfalin.…”

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confidence: 99%

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Transport of the phosphonodipeptide alafosfalin by the H⁺/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Neumann¹,

Bruch²,

Gebauer

et al. 2004

European Journal of Biochemistry

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The interaction of the antibacterial phosphonodipeptide alafosfalin with mammalian H + /peptide cotransporters was studied in Caco-2 cells, expressing the low-affinity intestinal type peptide transporter 1 (PEPT1), and SKPT cells, expressing the high-affinity renal type peptide transporter 2 (PEPT2). Alafosfalin strongly inhibited the uptake of [ 14 C]glycylsarcosine with K i values of 0.19 ± 0.01 mM and 0.07 ± 0.01 mM for PEPT1 and PEPT2, respectively. Saturation kinetic studies revealed that in both cell types alafosfalin affected only the affinity constant (K t ) but not the maximal velocity (V max ) of glycylsarcosine (Gly-Sar) uptake. The inhibition constants and the competitive nature of inhibition were confirmed in Dixon-type experiments. Caco-2 cells and SKPT cells were also cultured on permeable filters: apical uptake and transepithelial apical to basolateral flux of [ 14 C]Gly-Sar across Caco-2 cell monolayers were reduced by alafosfalin (3 mM) by 73%. In SKPT cells, uptake of [ 14 C]Gly-Sar but not flux was inhibited by 61%. We found no evidence for an inhibition of the basolateral to apical uptake or flux of [ 14 C]Gly-Sar by alafosfalin. Alafosfalin (3 mM) did not affect the apical to basolateral [ 14 C]mannitol flux. Determined in an Ussing-type experiment with Caco-2 cells cultured in Snapwells TM , alafosfalin increased the shortcircuit current through Caco-2 cell monolayers. We conclude that alafosfalin interacts with both H + /peptide symporters and that alafosfalin is actively transported across the intestinal epithelium in a H + -symport, explaining its oral availability. The results also demonstrate that dipeptides where the C-terminal carboxyl group is substituted by a phosphonic function represent high-affinity substrates for mammalian H + /peptide cotransporters.Keywords: alafosfalin; alaphosphin; Caco-2 cells; SKPT cells; Ussing technique.Alafosfalin (alaphosphin, L-alanyl-L-1-aminoethylphosphonic acid) is an antibacterial dipeptide analogue where the carboxyl group at the C-terminal alanine is replaced with a phosphonic [P(O)(OH) 2 ] function. The compound was one of the most promising aminophosphonic acids obtained in an extensive study synthesizing more than 300 di-to penta-peptide alanine mimetics with varying stereometry and different substituents for the C-terminal carboxyl function [1]. It displays good oral availability, substantial antibacterial activity mainly against Gramnegative bacteria and synergism with b-lactam antibiotics [1][2][3][4][5]. In clinical studies alafosfalin was tested for the treatment of gastrointestinal [3] and urinary tract infections [2,4]. Studies demonstrated the competitive effect of food on its enzymatic breakdown in the intestinal lumen [6]. In a recent publication Kafarski & Lejczak [7] reviewed the potential medical importance of aminophosphonic acids and conclude that, due to their negligible mammalian toxicity and the fact that they very efficiently mimic aminocarboxylic acids making them extremely important antimetabolites, aminophosphonic aci...

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Section: Transport Of Alafosfalin -Short-circuit Current Measurementsmentioning

confidence: 99%

“…It does not necessarily mean that the phosphonodipeptide is actually transported into the cells. Interaction with PEPT1 and PEPT2, the fact that bacterial permeases take up alafosfalin [11–14] and the known oral availability of alafosfalin, can only be regarded as circumstantial evidence for actual transport. Therefore, we exploited the electrogenic nature of H + /peptide symporters in an Ussing‐type of experiment to obtain more direct evidence.…”

Section: Transport Of Alafosfalin – Short‐circuit Current Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

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Transport of the phosphonodipeptide alafosfalin by the H⁺/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Neumann¹,

Bruch²,

Gebauer

et al. 2004

European Journal of Biochemistry

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“…L-4-chlorokynurenine was shown to be rapidly delivered into the brain by the large neutral amino acid transporter of the blood-brain barrier and to be converted intracellularly to its parent drug, 7chlorokynurenic acid (42). Furthermore, there have been some reports on prodrug design targeting peptide transporters, including peptidyl derivatives of a-methyldopa and alafosfalin and tripeptidyl prodrugs of foscarnet (43)(44)(45).…”

Section: Prodrug Design Targeting the Membrane Transportersmentioning

confidence: 99%

Targeted prodrug design to optimize drug delivery

Han¹,

2000

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Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific membrane transporter, or both, has potential as a selective drug delivery system in cancer chemotherapy or as an efficient oral drug delivery system. Site-selective targeting with prodrugs can be further enhanced by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody-directed enzyme prodrug therapy, genedirected enzyme prodrug therapy, and peptide transporter-associated prodrug therapy.

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Distribution: Movement of Drugs through the Body

Panyam

Patil

2010

Pharmaceutical Sciences Encyclopedia

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Drug distribution refers to the reversible movement of drug from blood to various tissues of the body. Following entry into the systemic circulation, a drug distributes into different tissues, the rate and extent of which is dependent on the drug's physicochemical properties and the blood flow to the tissues. This article focuses on the various factors affecting drug distribution and the different approaches available to modify drug distribution.

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Activity of a peptidyl prodrug, alafosfalin, against anaerobic bacteria

Cited by 11 publications

References 8 publications

Transport of the phosphonodipeptide alafosfalin by the H⁺/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Transport of the phosphonodipeptide alafosfalin by the H⁺/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Targeted prodrug design to optimize drug delivery

Distribution: Movement of Drugs through the Body

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Activity of a peptidyl prodrug, alafosfalin, against anaerobic bacteria

Cited by 11 publications

References 8 publications

Transport of the phosphonodipeptide alafosfalin by the H+/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Transport of the phosphonodipeptide alafosfalin by the H+/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Targeted prodrug design to optimize drug delivery

Distribution: Movement of Drugs through the Body

Contact Info

Product

Resources

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Transport of the phosphonodipeptide alafosfalin by the H⁺/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells

Transport of the phosphonodipeptide alafosfalin by the H⁺/peptide cotransporters PEPT1 and PEPT2 in intestinal and renal epithelial cells