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首页> 外文学位 >Design of prodrugs of acyclovir for ocular, oral and genital herpes virus infections: Targeting the oligopeptide and amino acid transporter on the cornea and intestine for improved bioavailability, safety and therapeutic activity.
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Design of prodrugs of acyclovir for ocular, oral and genital herpes virus infections: Targeting the oligopeptide and amino acid transporter on the cornea and intestine for improved bioavailability, safety and therapeutic activity.

机译：阿昔洛韦用于眼，口腔和生殖器疱疹病毒感染的前药设计：针对角膜和肠道上的寡肽和氨基酸转运蛋白，以提高生物利用度，安全性和治疗活性。

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摘要

Infection with herpes simplex virus is the single most frequent cause of corneal opacities in developed countries. Currently available therapy for HSV keratitis involves the use of trifluorothymidine, idoxuridine and vidarabine. However, one of the major problems associated with these drugs is their poor ocular absorption and cytotoxicity restricting their use in long-term treatment. L-Valyl ester prodrug of Acyclovir (ACV), valacyclovir (VACV) has been indicated in the treatment of genital herpes, the incidence of which has increased significantly in the last 20 years. Although genital herpes is self-limiting in healthy adults, the disease is painful and distressing, with severe psychosocial impact. Thus, the development of a safe, long-acting, effective, non-toxic, and stable topical antiviral drops and oral formulations that require less frequent dosing for fewer days or lower concentrations would represent a significant improvement over the currently available antivirals used against ocular, oral and genital HSV infections.;Recently significant amount of work has been reported on substrate specificities of membrane transporters and receptors leading to successful design of prodrugs targeted to them for improved efficacy and absorption. VACV is such a prodrug that is recognized by the peptide transporter, hPEPT1 resulting in enhancement of oral bioavailability of acyclovir by three to five fold in humans. Utilizing transporters present on the corneal epithelium may enhance corneal permeability of polar compounds. The presence of an oligopeptide and amino acid transport system on the corneal epithelium has been established. A series of novel water-soluble dipeptide and amino acid ester prodrugs of acyclovir were thus synthesized in order to target the transporters on the cornea for improved ocular bioavailability of acyclovir. These prodrugs once transported across or influxed into the target cells undergo chemical as well as enzymatic hydrolysis to release the active parent drug, ACV.;In conclusion more permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and antiviral activity against herpes simplex viruses. These prodrugs also demonstrated higher bioavailability upon topical as well as oral administration, thereby rendering these compounds promising drug candidates against ocular, oral and genital herpes infections.
机译：在发达国家，单纯疱疹病毒感染是角膜混浊的最常见原因。 HSV角膜炎的当前可用疗法包括使用三氟胸苷，异氧尿苷和维达拉滨。然而，与这些药物有关的主要问题之一是它们不良的眼吸收和细胞毒性，限制了它们在长期治疗中的使用。阿昔洛韦（ACV），伐昔洛韦（VACV）的L-戊酸酯前药已被用于治疗生殖器疱疹，在最近20年中其发生率显着增加。尽管生殖器疱疹在健康的成年人中是自限性的，但该疾病痛苦且令人痛苦，具有严重的社会心理影响。因此，开发一种安全，长效，有效，无毒且稳定的局部用抗病毒滴剂和需要减少给药频率，减少使用天数或降低浓度的口服制剂，将明显优于目前使用的抗眼用抗病毒药；口腔和生殖器HSV感染。；最近有关膜转运蛋白和受体的底物特异性的大量工作报道，导致成功设计出针对它们的前药以提高功效和吸收。 VACV是一种被肽转运蛋白hPEPT1识别的前药，可导致阿昔洛韦在人类中的口服生物利用度提高三到五倍。利用存在于角膜上皮上的转运蛋白可以增强极性化合物的角膜通透性。已经确定在角膜上皮上存在寡肽和氨基酸转运系统。因此合成了一系列新的阿昔洛韦水溶性二肽和氨基酸酯前药，以靶向角膜上的转运蛋白以改善阿昔洛韦的眼生物利用度。这些前药一旦跨过靶细胞或流入靶细胞后，会进行化学水解和酶水解以释放活性母体药物ACV。总而言之，更具渗透性，细胞毒性较小的ACV二肽前药表现出出色的化学稳定性和对单纯疱疹病毒的抗病毒活性。这些前药在局部和口服给药时也显示出更高的生物利用度，从而使这些化合物有望成为针对眼，口腔和生殖器疱疹感染的候选药物。

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  • 作者

    Anand, Banmeet Singh.;

  • 作者单位

    University of Missouri - Kansas City.;

  • 授予单位 University of Missouri - Kansas City.;
  • 学科 Pharmaceutical sciences.;Pharmacology.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 260 p.
  • 总页数 260
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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