Novel Biotinylated Lipid Prodrugs of Acyclovir for the Treatment of Herpetic Keratitis (HK): Transporter Recognition, Ti
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RESEARCH PAPER
Novel Biotinylated Lipid Prodrugs of Acyclovir for the Treatment of Herpetic Keratitis (HK): Transporter Recognition, Tissue Stability and Antiviral Activity Aswani Dutt Vadlapudi & Ramya Krishna Vadlapatla & Ravinder Earla & Suman Sirimulla & Jake Brain Bailey & Dhananjay Pal & Ashim K. Mitra Received: 20 December 2012 / Accepted: 10 April 2013 # Springer Science+Business Media New York 2013
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-RACV 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.
A. D. Vadlapudi : R. K. Vadlapatla : R. Earla : D. Pal : A. K. Mitra (*) Division of Pharmaceutical Sciences, School of Pharmacy University of Missouri-Kansas City, 2464 Charlotte Street Kansas City, Missouri 64108, USA e-mail: [email protected] S. Sirimulla : J. B. Bailey Department of Chemistry & Biochemistry Northern Arizona University, Flagstaff, Arizona 86011, USA
KEY WORDS acyclovir . cornea . antiviral activity . herpetic keratitis . SMVT ABBREVIATIONS 12HS-ACV 12hydroxystearicacid-acyclovir ACV Acyclovir B-12HS-ACV Biotin-12hydroxystearicacid-acyclovir B-ACV Biotin-acyclovir B-R-ACV Biotin-ricinoleicacid-acyclovir EBV Epstein - Barr virus HCEC Human corneal epithelial cells HCMV Human cytomegalovirus HK Herpetic keratitis HSV Herpes simplex virus LC/MS/MS Liquid chromatography-tandem mass spectrometry R-ACV Ricinoleicacid-acyclovir rPCEC Rabbit primary corneal epithelial cells SMVT Sodium dependent multivitamin transporter
INTRODUCTION Herpetic keratitis (HK) is a serious corneal complication which can lead to blindness, predominantly because of its recurrent nature (1–3). HK is caused by herpes simplex virus (HSV), a DNA virus that commonly affects humans. Herpes viruses are categorized into two t
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