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首页> 美国卫生研究院文献>Ophthalmology and Eye Diseases >Small Neutral Amino Acid Ester Prodrugs of Acyclovir Targeting Amino Acid Transporters on the Cornea: Possible Antiviral Agents Against Ocular HSV-1 Infections
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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

机译：阿昔洛韦的小中性氨基酸酯前体靶向角膜上的氨基酸转运蛋白：可能的抗病毒剂对眼HSV-1感染。

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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 [3H] 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 (B0,+). 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.
机译：这项研究的目的是表征无环鸟苷（ACV），L-丙氨酸-ACV（AACV），L-丝氨酸-ACV（SACV），L-丝氨酸-琥珀酸酯-ACV的氨基酸酯前药的亲和力和渗透性模式（SSACV）和L-半胱氨酸-ACV（CACV）在兔原代角膜上皮细胞培养物（rPCEC）和兔角膜上。在我们的实验室中合成了阿昔洛韦，AACV，SACV，SSACV和CACV的氨基酸前药。研究了在水性缓冲液中的化学水解，在角膜匀浆中的酶促水解以及这些前药在新鲜切下的兔角膜中的转运。 SSACV抑制rPCEC和整个兔角膜摄取[ 3 H] L-丙氨酸。 Lineweaver-Burk图变换显示了L-丙氨酸和SSACV之间的竞争抑制作用。在角膜组织匀浆中，SSACV，SACV和CACV的半衰期（t1 / 2）分别为3.5±0.4、9.2±0.6和1.8±0.1小时，而AACV易于转化为活性完全的阿昔洛韦，表现出完全的5分钟前降解。有趣的是，在5 mM精氨酸（〜51％）（一种阳离子转运系统的特异性底物）和BCH（〜38％）（一种大型中性氨基酸转运系统的特异性底物）的存在下，SACV在角膜上的转运受到抑制。 LAT）或阳离子和中性氨基酸转运系统（B 0，+ ）。与ACV相比，SACV表现出更高的跨角膜通透性以及对单纯疱疹病毒（HSV-1）和水痘带状疱疹病毒（VZV）的优异抗病毒活性。多种转运蛋白的识别，角膜匀浆的稳定性以及理化性质的变化有助于SACV跨角膜通透性的提高。

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