Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: Interactions with the neutral and cationic amino acid transporter on the corneal epithelium
Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: Interactions with the neutral and cationic amino acid transporter on the corneal epithelium
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DOI：
10.1080/02713680490504614
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发表时间：
2004-08-01
影响因子：
2
通讯作者：
Mitra, AK
中科院分区：
文献类型：
--
作者：
Anand, BS;Katragadda, S;Mitra, AK
目的。本研究的目的是通过设计针对兔角膜氨基酸转运体的氨基酸前药，探讨提高抗病毒药物阿昔洛韦眼部生物利用度的可行性。本文研究了两种水溶性氨基酸酯类药物阿昔洛韦(阿昔洛韦)-谷氨酸-阿昔洛韦和L-酪氨酸-阿昔洛韦在新鲜离体兔角膜上的通透性。并对两种前药进行了化学和酶促水解研究。阿昔洛韦抑制兔原代角膜上皮细胞摄取[H-3]L-精氨酸。与YACV相比，该化合物在角膜中的半衰期更长(t(1/2))。在所研究的范围内，EACV的角膜通透性与浓度、能量和钠有关，与pH无关。中性氨基酸和阳离子氨基酸、L鸟氨酸(阳离子氨基酸特异性)和Bch(2-aminobicyclo-[2，2，1]-heptane-2-carboxylic-acid)(L系统和B-0，B-+系统特异性抑制剂)均能抑制EACV的转运。另一方面，YACV不能被这个氨基酸转运蛋白识别，因为它不能抑制[H-3]Arg的摄取，而且它的跨角膜转运也不被精氨酸抑制。YACV和EACV对HSV-1、HSV-2和水痘-带状疱疹病毒(VZV)的抗病毒活性均优于ACV。对EACV转运抑制模式的分析表明，只有一个转运系统参与其中，即B-0，B-+。设计氨基酸前体药物似乎是一种有吸引力的策略，以提高原本较难溶于水的化合物的溶解性，并提供靶向并可能增强活性药物的输送。
Purpose. The aim of this study was to explore the feasibility of improvement of ocular bioavailability of the antiviral agent acyclovir by designing amino acid prodrugs targeted to the amino acid transporters on the rabbit cornea.Materials and methods. Transcorneal flux of two water-soluble amino acid ester prodrugs of acyclovir (ACV), T-glutamate-ACV (EACV) and L-tyrosine-ACV (YACV), was studied across freshly excised rabbit cornea. Chemical and enzymatic hydrolysis studies of the two prodrugs were also conducted.Results. EACV inhibited the uptake of [H-3]L-Arg in rabbit primary corneal epithelial cells (rPCECs). The compound also exhibited longer half-life (t(1/2)) in cornea in comparison to YACV Transcorneal flux of EACV was observed to be concentration-, energy-, and sodium-dependent and independent of pH within the range studied. EACV transport was inhibited by neutral and cationic amino acids, L-ornithine (specific for cationic amino acids), and BCH (2-aminobicyclo-[2,2,1]-heptane-2-carboxylic-acid) (specific inhibitor for L-type system and B-0,B-+ system). On the other hand, YACV was not recognized by this amino acid transporter as it failed to inhibit the uptake of [H-3]Arg, and also its transport across cornea was not inhibited by arginine. YACV and EACV exhibited excellent antiviral activity against HSV-1 and 2 and Varicella-Zoster Virus (VZV) in comparison to ACV.Conclusions. Analyses of the inhibition pattern of EACV transport suggests the involvement of a single transport system; namely, B-0,B-+. Design of amino acid prodrugs seems to be an attractive strategy to enhance the solubility of the otherwise poorly aqueous soluble compounds and also to afford a targeted and possibly enhanced delivery of the active drug.