Novel prodrugs for treatment of human CMV infection

描述（由申请人提供）：由于抗病毒预防和先发制人治疗的广泛使用，人类巨细胞病毒（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耐药性。特别是，随着口服更昔洛韦（GCV）预防丙型肝炎病毒的出现，人们开始关注丙型肝炎病毒耐药性（GCV- r）的出现。磷酸核苷酸类药物如西多福韦（CDV）和9-(S)-（3-羟基-2-磷酸异氧基丙基）腺嘌呤（HPMPA）可成功治疗GCV-R。然而，这些药物作为口服治疗药物有很大的局限性，因为作为一个群体，它们在口服时吸收不良。我们已经开发了一种药物前策略，旨在改善磷酸核苷酸药物、CDV和HPMPA的口服吸收，使它们成为有效的抗hcmv口服治疗剂。在项目一期中，我们拟合成一系列新的CDV和HPMPA前药，并评价其对CMV敏感株和GCV-R耐药株的稳定性、代谢和抗病毒活性。对稳定性好、代谢简化的前药进行口服生物利用度试验。这项工作将为开发一种有效的口服抗更昔洛韦耐药HCMV药物奠定科学基础。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。

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.