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Novel Biotinylated Lipid Prodrugs of Acyclovir for the Treatment of Herpetic Keratitis (HK): Transporter Recognition, Tissue Stability and Antiviral Activity

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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.

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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

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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.

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA

    Aswani Dutt Vadlapudi, Ramya Krishna Vadlapatla, Ravinder Earla, Dhananjay Pal & Ashim K. Mitra

  2. Department of Chemistry & Biochemistry, Northern Arizona University, Flagstaff, Arizona, 86011, USA

    Suman Sirimulla & Jake Brain Bailey

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  1. Aswani Dutt Vadlapudi
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Correspondence to Ashim K. Mitra.

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Vadlapudi, A.D., Vadlapatla, R.K., 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 30, 2063–2076 (2013). https://doi.org/10.1007/s11095-013-1059-7

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