Ganapathy M E, Ganapathy V
Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
Curr Drug Targets Immune Endocr Metabol Disord. 2005 Dec;5(4):357-64. doi: 10.2174/156800805774912953.
ATB(0,+) is a unique amino acid transporter because of its broad substrate specificity and concentrative ability. This transporter recognizes neutral as well as cationic amino acids. It is energized by Na(+) and Cl(-) gradients and membrane potential. Many of the amino acids and amino acid derivatives that are substrates for ATB(0,+) serve as therapeutic agents (e.g., D-serine, carnitine, and nitric oxide synthase inhibitors). Recent studies have shown that the potential of ATB(0,+) as a drug delivery system may be greater than previously envisaged. ATB(0,+) can transport antiviral drugs such as acyclovir and ganciclovir when they are covalently coupled to the side chain of anionic amino acids. Chemical modification of the carboxyl groups in the side chain of aspartate and glutamate with drugs converts these anionic amino acids into neutral amino acid derivatives. Therefore, the modified drugs are recognized by ATB(0,+). Interestingly, even when acyclovir and ganciclovir are coupled as esters with alpha-carboxyl group of neutral amino acids, the modified drugs are transported via ATB(0,+). Similarly, the hydroxyl group in the side chains of serine and threonine can also be used to covalently couple drugs for delivery into cells via ATB(0,+). This increases the potential for designing a wide variety of amino acid-based prodrugs that can utilize ATB(0,+) as drug delivery system. Furthermore, the transporter is expressed in the colon, lung, and eye, the tissues easily amenable for drug delivery. These findings argue strongly in support of ATB(0,+) as a potential delivery system for a wide variety of drugs and prodrugs.
ATB(0,+)是一种独特的氨基酸转运体，因其具有广泛的底物特异性和浓缩能力。该转运体识别中性和阳离子氨基酸。它由Na(+)和Cl(-)梯度以及膜电位提供能量。许多作为ATB(0,+)底物的氨基酸和氨基酸衍生物可作为治疗剂（例如，D-丝氨酸、肉碱和一氧化氮合酶抑制剂）。最近的研究表明，ATB(0,+)作为药物递送系统的潜力可能比之前设想的更大。当抗病毒药物阿昔洛韦和更昔洛韦与阴离子氨基酸的侧链共价偶联时，ATB(0,+)可以转运它们。用药物对天冬氨酸和谷氨酸侧链中的羧基进行化学修饰，可将这些阴离子氨基酸转化为中性氨基酸衍生物。因此，修饰后的药物可被ATB(0,+)识别。有趣的是，即使阿昔洛韦和更昔洛韦与中性氨基酸的α-羧基以酯的形式偶联，修饰后的药物也能通过ATB(0,+)进行转运。同样，丝氨酸和苏氨酸侧链中的羟基也可用于共价偶联药物，以便通过ATB(0,+)递送至细胞内。这增加了设计多种基于氨基酸的前药的可能性，这些前药可将ATB(0,+)用作药物递送系统。此外，该转运体在结肠、肺和眼睛中表达，这些组织易于进行药物递送。这些发现有力地支持了ATB(0,+)作为多种药物和前药的潜在递送系统。
