title: Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity.
abstract: OBJECTIVE
  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: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, USA.
authors: Aswani Dutt
authors: AD
authors: Vadlapudi
authors: Ramya Krishna
authors: RK
authors: Vadlapatla
authors: Ravinder
authors: R
authors: Earla
authors: Suman
authors: S
authors: Sirimulla
authors: Jake Brain
authors: JB
authors: Bailey
authors: Dhananjay
authors: D
authors: Pal
authors: Ashim K
authors: AK
authors: Mitra
mesh_terms: D000212:Acyclovir / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019921:Biotinylation; D002460:Cell Line; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D027981:Symporters / Q000378:metabolism*; D014777:Virus Diseases / Q000188:drug therapy; D014780:Viruses / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D027981:Symporters; C119981:biotin transporter; D000212:Acyclovir
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