Novel prodrugs for treatment of human CMV infection

描述（由申请方提供）：由于抗病毒预防和预防性治疗的广泛使用，人巨细胞病毒（HCMV）疾病的发病率和严重程度及其间接影响已显著降低。然而，人们越来越认识到抗病毒药物的耐药性。特别是，随着口服更昔洛韦（GCV）预防HCMV的出现，对GCV耐药（GCV-R）的出现的担忧已经提出。GCV-R可以用核苷酸膦酸酯药物如西多福韦（CDV）和9-（S）-（3-羟基-2-膦酰甲氧基-丙基）腺嘌呤（HPMPA）成功治疗。然而，这些药物作为口服治疗剂受到显著限制，因为作为一个组，它们在口服给药时吸收不良。我们已经开发了一种前药策略，旨在改善核苷酸膦酸盐药物CDV和HPMPA的口服吸收，使它们成为有效的抗HCMV口服治疗剂。在该项目的第1阶段部分，我们建议合成一系列新的CDV和HPMPA前药，并评估其稳定性、代谢和抗CMV敏感株和GCV-R抗性株的抗病毒活性。将测试显示良好稳定性和简化代谢的那些前药的口服生物利用度。本研究为开发更昔洛韦耐药的口服抗HCMV药物奠定了科学基础。在这个项目中，我们与南加州大学的Charles McKenna教授（前药设计和合成）和密歇根大学的John Drach教授（病毒学研究）建立了合作关系。 公共卫生相关性：对有效对抗人巨细胞病毒的耐药株的新药的需求日益增加，随着针对病毒的长期治疗的开发，耐药株变得越来越多。一系列新的药物是可用的，但它们不适合商业化，因为它们在口服时不能很好地吸收。因此，这项工作的目标是修改这些新药，使它们在口服时吸收良好，并对人类巨细胞病毒有效。

DESCRIPTION (provided by applicant): As a result of the widespread use of antiviral prophylaxis and pre-emptive therapy, the incidence and severity of human cytomegalovirus (HCMV) disease and its indirect effects have been significantly reduced. However, there is an increasing recognition of antiviral drug resistance. In particular, with the advent of oral ganciclovir (GCV) prophylaxis against HCMV, concerns about emergence of GCV resistance (GCV-R) have been raised. GCV-R can be successfully treated with nucleotide phosphonate drugs such as Cidofovir (CDV) and 9-(S)-(3- hydroxy-2-phosphonomethoxy-propyl)adenine (HPMPA). However, these drugs are significantly limited as oral therapeutics because, as a group, they are poorly absorbed when administered orally. We have developed a prodrug strategy designed to improve the oral absorption of the nucleotide phosphonate drugs, CDV and HPMPA, such that they will be effective anti-HCMV oral therapeutic agents. In the phase 1 portion of the project, we propose to synthesize a novel series of CDV and HPMPA prodrugs and evaluate their stability, metabolism and antiviral activity against sensitive and GCV-R resistant strains of CMV. Those prodrugs showing good stability and simplified metabolism will be tested for oral bioavailability. This work will lay the scientific foundation for development of an effective, oral agent against ganciclovir resistant HCMV. For this project, we have established collaborations with Prof. Charles McKenna (prodrug design and synthesis) at the University of Southern California and Prof. John Drach (virological studies) at the University of Michigan. PUBLIC HEALTH RELEVANCE: There is an increasing need for new drugs that are effective against drug-resistant strains of the human cytomegalovirus that are becoming more numerous as long term treatments against the virus are developed. A series of new drugs is available but they are not suitable for commercialization because they are not well absorbed when given orally. Thus, the goal of this work is to modify these new drugs such that they are well absorbed when taken orally and will be effective against the human cytomegalovirus.