Novel Biotinylated Lipid Prodrugs of Acyclovir for the Treatment of Herpetic Keratitis (HK): Transporter Recognition, Tissue Stability and Antiviral Activity
- 464 Downloads
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.
All the prodrugs were screened for in vitro cellular uptake, interaction with SMVT, docking analysis, cytotoxicity, enzymatic stability and antiviral activity.
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.
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.
KEY WORDSacyclovir cornea antiviral activity herpetic keratitis SMVT
Epstein - Barr virus
Human corneal epithelial cells
Herpes simplex virus
Liquid chromatography-tandem mass spectrometry
Rabbit primary corneal epithelial cells
Sodium dependent multivitamin transporter
ACKNOWLEDGMENTS AND DISCLOSURES
We would like to acknowledge Dr. Mark Prichard at The University of Alabama at Birmingham (UAB) for conducting the in vitro antiviral screening studies under NIH/NIAID contract. Also, we would like to thank Dr. Christopher Tseng and Miriam Perkins at National Institute of Allergy and Infectious Diseases (NIAID) for their support. This work has been supported by NIH grant R01EY009171. All these prodrugs are currently under investigation by NIH/NIAID for screening the in vivo antiviral efficacy in virus infected animal models.
- 8.Vadlapudi AD, Vadlapatla RK. Mitra AK. Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective. Recent Pat Antiinfect Drug Discov. 2013;8(1):55–67.Google Scholar
- 10.Kennedy DP, Clement C, Arceneaux RL, Bhattacharjee PS, Huq TS, Hill JM. Ocular Herpes Simplex Virus Type 1: Is the Cornea a Reservoir for Viral Latency or a Fast Pit Stop? Cornea. 2010. doi: 10.1097/01.ico.0000391265.52134.f0
- 40.Earla R, Boddu SH, Cholkar K, Hariharan S, Jwala J, Mitra AK. Development and validation of a fast and sensitive bioanalytical method for the quantitative determination of glucocorticoids–quantitative measurement of dexamethasone in rabbit ocular matrices by liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal. 2010;52(4):525–33.PubMedCrossRefGoogle Scholar
- 47.Talluri RS, Hariharan S, Karla PK, Mitra AK. Drug delivery to cornea and conjunctiva-esterase and protease directed prodrug design. In: Dartt DA, Bex P, D’Amore P, Dana R, Mcloon L & Niederkorn J, editors. Ocular Periphery and Disorders. San Deigo, California, USA: Elsevier, Academic Press Elsevier Ltd; 2011. p. 303–314.Google Scholar
- 48.Atluri H, Tirucherai GS, Dias CS, Patel J, Mitra AK. Ocular, Nasal, Pulmonary, and Otic Routes of Drug Delivery. In: Bhaskara R, Jasti and Tapash K, editors. Theory and Practice of Contemporary Pharmaceutics, Ghosh, CRC Press; 2004. p. 479–524.Google Scholar