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Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity.
Pharm Res. 2013 Aug; 30(8):2063-76.PR

Abstract

PURPOSE

Biotinylated lipid prodrugs of acyclovir (ACV) were designed to target the sodium dependent multivitamin transporter (SMVT) on the cornea to facilitate enhanced cellular absorption of ACV.

METHODS

All the prodrugs were screened for in vitro cellular uptake, interaction with SMVT, docking analysis, cytotoxicity, enzymatic stability and antiviral activity.

RESULTS

Uptake of biotinylated lipid prodrugs of ACV (B-R-ACV and B-12HS-ACV) was significantly higher than biotinylated prodrug (B-ACV), lipid prodrugs (R-ACV and 12HS-ACV) and ACV in corneal cells. Transepithelial transport across rabbit corneas indicated the recognition of the prodrugs by SMVT. Average Vina scores obtained from docking studies further confirmed that biotinylated lipid prodrugs possess enhanced affinity towards SMVT. All the prodrugs studied did not cause any cytotoxicity and were found to be safe and non-toxic. B-R-ACV and B-12HS-ACV were found to be relatively more stable in ocular tissue homogenates and exhibited excellent antiviral activity.

CONCLUSIONS

Biotinylated lipid prodrugs demonstrated synergistic improvement in cellular uptake due to recognition of the prodrugs by SMVT on the cornea and lipid mediated transcellular diffusion. These biotinylated lipid prodrugs appear to be promising drug candidates for the treatment of herpetic keratitis (HK) and may lower ACV resistance in patients with poor clinical response.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23657675

Citation

Vadlapudi, Aswani Dutt, et al. "Novel Biotinylated Lipid Prodrugs of Acyclovir for the Treatment of Herpetic Keratitis (HK): Transporter Recognition, Tissue Stability and Antiviral Activity." Pharmaceutical Research, vol. 30, no. 8, 2013, pp. 2063-76.
Vadlapudi AD, Vadlapatla RK, Earla R, et al. Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity. Pharm Res. 2013;30(8):2063-76.
Vadlapudi, A. D., Vadlapatla, R. K., Earla, R., Sirimulla, S., Bailey, J. B., Pal, D., & Mitra, A. K. (2013). Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity. Pharmaceutical Research, 30(8), 2063-76. https://doi.org/10.1007/s11095-013-1059-7
Vadlapudi AD, et al. Novel Biotinylated Lipid Prodrugs of Acyclovir for the Treatment of Herpetic Keratitis (HK): Transporter Recognition, Tissue Stability and Antiviral Activity. Pharm Res. 2013;30(8):2063-76. PubMed PMID: 23657675.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity. AU - Vadlapudi,Aswani Dutt, AU - Vadlapatla,Ramya Krishna, AU - Earla,Ravinder, AU - Sirimulla,Suman, AU - Bailey,Jake Brain, AU - Pal,Dhananjay, AU - Mitra,Ashim K, Y1 - 2013/05/09/ PY - 2012/12/20/received PY - 2013/04/10/accepted PY - 2013/5/10/entrez PY - 2013/5/10/pubmed PY - 2014/1/28/medline SP - 2063 EP - 76 JF - Pharmaceutical research JO - Pharm. Res. VL - 30 IS - 8 N2 - PURPOSE: Biotinylated lipid prodrugs of acyclovir (ACV) were designed to target the sodium dependent multivitamin transporter (SMVT) on the cornea to facilitate enhanced cellular absorption of ACV. METHODS: All the prodrugs were screened for in vitro cellular uptake, interaction with SMVT, docking analysis, cytotoxicity, enzymatic stability and antiviral activity. RESULTS: Uptake of biotinylated lipid prodrugs of ACV (B-R-ACV and B-12HS-ACV) was significantly higher than biotinylated prodrug (B-ACV), lipid prodrugs (R-ACV and 12HS-ACV) and ACV in corneal cells. Transepithelial transport across rabbit corneas indicated the recognition of the prodrugs by SMVT. Average Vina scores obtained from docking studies further confirmed that biotinylated lipid prodrugs possess enhanced affinity towards SMVT. All the prodrugs studied did not cause any cytotoxicity and were found to be safe and non-toxic. B-R-ACV and B-12HS-ACV were found to be relatively more stable in ocular tissue homogenates and exhibited excellent antiviral activity. CONCLUSIONS: Biotinylated lipid prodrugs demonstrated synergistic improvement in cellular uptake due to recognition of the prodrugs by SMVT on the cornea and lipid mediated transcellular diffusion. These biotinylated lipid prodrugs appear to be promising drug candidates for the treatment of herpetic keratitis (HK) and may lower ACV resistance in patients with poor clinical response. SN - 1573-904X UR - https://www.unboundmedicine.com/medline/citation/23657675/Novel_biotinylated_lipid_prodrugs_of_acyclovir_for_the_treatment_of_herpetic_keratitis__HK_:_transporter_recognition_tissue_stability_and_antiviral_activity_ L2 - https://doi.org/10.1007/s11095-013-1059-7 DB - PRIME DP - Unbound Medicine ER -