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Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters on the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections.
Ophthalmol Eye Dis. 2010; 2:43-56.OE

Abstract

The aim of this study was to characterize the affinity and permeability patterns of the amino acid ester prodrugs of acyclovir (ACV), L-alanine-ACV (AACV), L-serine-ACV (SACV), L-serine-succinate-ACV (SSACV) and L-cysteine-ACV (CACV) on rabbit primary corneal epithelial cell culture (rPCEC) and on rabbit cornea. Amino acid prodrugs of acyclovir, AACV, SACV, SSACV and CACV were synthesized in our laboratory. Chemical hydrolysis in aqueous buffer, enzymatic hydrolysis in corneal homogenates and transport across freshly excised rabbit cornea of these prodrugs were studied. SSACV inhibited the uptake of [(3)H] L-alanine on rPCEC and across the intact rabbit cornea. Lineweaver-Burk plot transformation revealed competitive inhibition between L-alanine and SSACV. In corneal tissue homogenate, the half lives of SSACV, SACV and CACV (t1/2) were observed to be 3.5 ± 0.4, 9.2 ± 0.6 and 1.8 ± 0.1 hr respectively, whereas AACV was readily converted to the active parent drug acyclovir exhibiting complete degradation before 5 min. Interestingly translocation of SACV across cornea was inhibited in the presence of 5 mM arginine (~51%), a specific substrate for cationic transport system and in presence of BCH (~38%), a substrate specific for large neutral amino acid transport system (LAT) or cationic and neutral amino acid transport system (B(0,+)). SACV exhibited higher permeability across cornea along with excellent antiviral activity against herpes simplex virus (HSV-1) and varicella-zoster virus (VZV) in comparison to ACV. Recognition by multiple transporters, stability in corneal homogenate and changes in physico-chemical properties contributed to the increased permeability of SACV across cornea.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23861613

Citation

Suresh, Katragadda, et al. "Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters On the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections." Ophthalmology and Eye Diseases, vol. 2, 2010, pp. 43-56.
Suresh K, Xiadong Z, Ravi TS, et al. Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters on the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections. Ophthalmol Eye Dis. 2010;2:43-56.
Suresh, K., Xiadong, Z., Ravi, T. S., & Mitra, A. K. (2010). Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters on the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections. Ophthalmology and Eye Diseases, 2, 43-56.
Suresh K, et al. Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters On the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections. Ophthalmol Eye Dis. 2010;2:43-56. PubMed PMID: 23861613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters on the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections. AU - Suresh,Katragadda, AU - Xiadong,Zhu, AU - Ravi,Talluri S, AU - Mitra,Ashim K, Y1 - 2010/07/29/ PY - 2013/7/18/entrez PY - 2010/1/1/pubmed PY - 2010/1/1/medline KW - acyclovir KW - amino acid conjugates KW - cornea KW - prodrug KW - transporter SP - 43 EP - 56 JF - Ophthalmology and eye diseases JO - Ophthalmol Eye Dis VL - 2 N2 - The aim of this study was to characterize the affinity and permeability patterns of the amino acid ester prodrugs of acyclovir (ACV), L-alanine-ACV (AACV), L-serine-ACV (SACV), L-serine-succinate-ACV (SSACV) and L-cysteine-ACV (CACV) on rabbit primary corneal epithelial cell culture (rPCEC) and on rabbit cornea. Amino acid prodrugs of acyclovir, AACV, SACV, SSACV and CACV were synthesized in our laboratory. Chemical hydrolysis in aqueous buffer, enzymatic hydrolysis in corneal homogenates and transport across freshly excised rabbit cornea of these prodrugs were studied. SSACV inhibited the uptake of [(3)H] L-alanine on rPCEC and across the intact rabbit cornea. Lineweaver-Burk plot transformation revealed competitive inhibition between L-alanine and SSACV. In corneal tissue homogenate, the half lives of SSACV, SACV and CACV (t1/2) were observed to be 3.5 ± 0.4, 9.2 ± 0.6 and 1.8 ± 0.1 hr respectively, whereas AACV was readily converted to the active parent drug acyclovir exhibiting complete degradation before 5 min. Interestingly translocation of SACV across cornea was inhibited in the presence of 5 mM arginine (~51%), a specific substrate for cationic transport system and in presence of BCH (~38%), a substrate specific for large neutral amino acid transport system (LAT) or cationic and neutral amino acid transport system (B(0,+)). SACV exhibited higher permeability across cornea along with excellent antiviral activity against herpes simplex virus (HSV-1) and varicella-zoster virus (VZV) in comparison to ACV. Recognition by multiple transporters, stability in corneal homogenate and changes in physico-chemical properties contributed to the increased permeability of SACV across cornea. SN - 1179-1721 UR - https://www.unboundmedicine.com/medline/citation/23861613/Small_Neutral_Amino_Acid_Ester_Prodrugs_of_Acyclovir_Targeting_Amino_Acid_Transporters_on_the_Cornea:_Possible_Antiviral_Agents_Against_Ocular_HSV_1_Infections_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23861613/ DB - PRIME DP - Unbound Medicine ER -
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