Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea

Anand, Banmeet; Nashed, Yasser E.; Mitra, Ashim K.

doi:10.1076/ceyr.26.3.151.14893

Cited by 58 publications

(69 citation statements)

References 13 publications

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“…The increase in the stability on incorporation of D-valine may be attributed to reduced affinity toward hydrolytic enzymes. Previous reports from Anand et al 10 clearly explained the bioconversion mechanism of dipeptide prodrugs. The dipeptide bond is hydrolyzed by the peptidases resulting in the regeneration of amino acid ester of ACV, which is further hydrolyzed by esterases regenerating the parent ACV.…”

Section: Discussionmentioning

confidence: 91%

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Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Jwala

Boddu

Shah

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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Purpose: The objective of this study was to develop and characterize polymeric nanoparticles of appropriate stereoisomeric dipeptide prodrugs of acyclovir (L-valine-L-valine-ACV, L-valine-D-valine-ACV, D-valine-Lvaline-ACV, and D-valine-D-valine-ACV) for the treatment of ocular herpes keratitis. Methods: Stereoisomeric dipeptide prodrugs of acyclovir (ACV) were screened for bioreversion in various ocular tissues, cell proliferation, and uptake across the rabbit primary corneal epithelial cell line. Docking studies were carried out to examine the affinity of prodrugs to the peptide transporter protein. Prodrugs with optimum characteristics were selected for the preparation of nanoparticles using various grades of poly (lactic-co-glycolic acid) (PLGA). Nanoparticles were characterized for the entrapment efficiency, surface morphology, size distribution, and in vitro release. Further, the effect of thermosensitive gels on the release of prodrugs from nanoparticles was also studied. Results: L-valine-L-valine-ACV and L-valine-D-valine-ACV were considered to be optimum in terms of enzymatic stability, uptake, and cytotoxicity. Docking results indicated that L-valine in the terminal position increases the affinity of the prodrugs to the peptide transporter protein. Entrapment efficiency values of Lvaline-L-valine-ACV and L-valine-D-valine-ACV were found to be optimal with PLGA 75:25 and PLGA 65:35 polymers, respectively. In vitro release of prodrugs from nanoparticles exhibited a biphasic release behavior with initial burst phase followed by sustained release. Dispersion of nanoparticles in thermosensitive gels completely eliminated the burst release phase. Conclusion: Novel nanoparticulate systems of dipeptide prodrugs of ACV suspended in thermosensitive gels may provide sustained delivery after topical administration.

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Section: Discussionmentioning

confidence: 91%

“…9 These dipeptide prodrugs (GVACV and VVACV) were found to be more permeable due to specific targeting toward PEPT and are considered as the potential candidates for the treatment of ocular HSV infections. 10 …”

Section: Introductionmentioning

confidence: 99%

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Jwala

Boddu

Shah

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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“…However, one of the major problems associated with these drugs is their poor ocular absorption, cytotoxicity, and mutagenicity, restricting their use in long-term treatment. Although the utility of valacyclovir against oral and genital herpes infections is well established and well documented (Fleming et al, 1997), it has not been used for topical application against ocular herpes infection, herpes simplex virus keratitis, probably due to a short half-life of ϳ72 h in pH 5.6 (Anand et al, 2002b). Various lipophilic prodrugs of nucleoside analog acyclovir have been studied for improved ocular absorption (Hughes and Mitra, 1993) to cure HSV keratitis.…”

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confidence: 99%

Interactions of the Dipeptide Ester Prodrugs of Acyclovir with the Intestinal Oligopeptide Transporter: Competitive Inhibition of Glycylsarcosine Transport in Human Intestinal Cell Line-Caco-2

Anand¹,

Patel²,

Mitra³

2003

J Pharmacol Exp Ther

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The oligopeptide transporter may be exploited to enhance the absorption of drugs by synthesizing their dipeptide ester prodrugs, which may be recognized as its substrates. Various dipeptide esters of acyclovir (ACV), an antiviral nucleoside analog, were synthesized. Enzymatic hydrolysis and affinity of the prodrugs toward the human intestinal peptide transporter hPEPT1 were studied using the human intestinal Caco-2 cell line. Affinity studies were performed by inhibiting the uptake of [ 3 H]glycylsarcosine by the prodrugs. The uptake of glycylsarcosine was found to be saturable at higher concentrations and was competitively inhibited by the prodrugs of ACV. All prodrugs except Tyr-Gly-ACV demonstrated a higher affinity (1.41-4.96 mM) toward hPEPT1 than cephalexin (8.19 Ϯ 2.12 mM), which was used as a positive control. Two prodrugs, Gly-Val-ACV and Val-Val-ACV, showed comparable affinity to Val-ACV, an amino acid prodrug of ACV recognized by PEPT1/PEPT2. The permeability of Gly-Val-ACV (2.99 Ϯ 0.59 ϫ 10 Ϫ6 cm/s) across Caco-2 was comparable with that of Val-ACV (3.01 Ϯ 0.21 ϫ 10 Ϫ6 cm/s) and was significantly inhibited (63%) in presence of glycylsarcosine. The transport of GVACV across Caco-2 was saturable at higher concentrations, and the parameters were calculated as K m 3.16 Ϯ 0.31 mM and V max 0.014 Ϯ 0.00058 nmol cm Ϫ2 min Ϫ1 . Overall, the results suggest that the dipeptide prodrugs of ACV have a high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of ocular and oral herpesvirus infections, because cornea and intestinal epithelia seem to express the oligopeptide transporters.

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“…Moreover, results obtained from this study are consistent with those observed for stereoisomeric prodrugs of saquinavir and acyclovir (32,33). Dipeptide prodrugs of acyclovir and ganciclovir have displayed significant improvements in transcorneal permeability relative to unmodified parent drugs (23,25,26,29,45). Half-lives displayed by LLACV, LDACV, and DLACV in intestinal homogenates are <0.08, 1, and 6 h, respectively.…”

Section: Cellular Uptake Studiesmentioning

confidence: 99%

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

2015

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Abstract. A series of stereoisomeric prodrugs have been designed to examine efficacy in generating higher corneal absorption relative to prednisolone. Prodrugs have been studied and identified with LC/MS/MS and NMR analyses. Prodrugs have been characterized for aqueous solubility, buffer stability, and cytotoxicity. Cellular uptake and permeability studies have been conducted across MDCK-MDR1 cells to determine prodrug affinity towards P-glycoprotein (P-gp) and peptide transporters. Enzyme-mediated degradation of prodrugs has been determined using Statens Seruminstitut rabbit cornea (SIRC) cell homogenates. Prodrugs exhibited higher aqueous solubility relative to prednisolone. Prodrugs circumvented P-gp-mediated cellular efflux and were recognized by peptide transporters. Prodrugs (DP, DDP) produced with D-isomers (D-valine) were significantly stable against both chemical and enzymatic hydrolyses. The order of degradation rate constants observed in chemical and enzymatic hydrolyses were in the same order, i.e., L-valine-L-valine-prednisolone (LLP)>L-valine-D-valine-prednisolone (LDP)>D-valine-L-valine-prednisolone (DLP)>D-valine-D-valine-prednisolone (DDP). Results obtained from this study clearly suggest that stereoisomeric prodrug approach is an effective strategy to overcome P-gpmediated efflux and improve transcorneal permeability of prednisolone following topical administration.

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Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea

Cited by 58 publications

References 13 publications

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

Interactions of the Dipeptide Ester Prodrugs of Acyclovir with the Intestinal Oligopeptide Transporter: Competitive Inhibition of Glycylsarcosine Transport in Human Intestinal Cell Line-Caco-2

Stereoisomeric Prodrugs to Improve Corneal Absorption of Prednisolone: Synthesis and In Vitro Evaluation

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