Novel inhibitors of the replication of poxviruses

痘病毒复制的新型抑制剂

• 批准号: 6845413
• 负责人: JOHAN H NEYTS
• 金额: $ 161.06万
• 依托单位: KATHOLIEKE UNIVERSITEIT LEUVEN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845413
• 关键词: Poxviridae; Poxviridae disease; SCID mouse; adenine analog; analog; antiviral agents; athymic mouse; bioterrorism /chemical warfare; cidofovir; cooperative study; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; nonhuman therapy evaluation; pharmacokinetics; phosphonate; tissue /cell culture; vaccinia virus; virus replication

DESCRIPTION (provided by applicant): It is of utmost important to have drugs at hand for the treatment of (i) smallpox, (ii) complications of vaccination against smallpox or (iii) monkeypox in humans. Currently only cidofovir, an acyclic nucleoside phosphonate (ANP), designed as an anti-herpes virus drug and used for the treatment of CMV retinitis, would be available for the treatment of poxvirus infections. The aims of this study are to design and synthesize ANPs that are even more potent and selective than cidofovir, that can be administered orally, and that have an excellent safety profile. We will focus on two structural types of parent compounds that we showed to be active in vitro and in vivo against poxviruses: (a) analogs of cidofovir and (b) "open-ring" analogues of HPMP-DAP. Modification of these lead structures should result in novel compounds with an enhanced anti-poxvirus activity and/or improved pharmacological parameters. Modification of cidofovir will take place at the cytosine base (substitution at the N-4 and C-5 positions), whereas in the "open-ring" series modifications will predominantly focus on the alteration of the 6-alkoxy chain bearing the structural features of the HPMP type (modifications of the alkyl chain, phosphonoalkoxy group, and hydroxymethyl group). The compounds will be prepared by the earlier developed methods for the synthesis of ANPs and will be evaluated for their inhibitory effect on the replication of various poxviruses. Compounds with an excellent safety profile, and that are, in addition, equally or more effective than cidofovir will be evaluated in various animal models for vaccinia virus infection. Compounds that prove in these animal models at least as effective as cidofovir will then be the subjects of detailed pharmacological, pharmacokinetic and toxicological studies. In addition prodrug will be prepared to allow excellent activity following oral administration. The final goal of this application is to advance a compound for the treatment of (systemic or cutaneous) poxvirus infections to the initial stages of development, i.e., selecting an IND candidate.

描述（由申请人提供）：最重要的是要把药物用于（i）天花，（ii）针对天花或（iii）蒙基托克的并发症在人类中。目前，只有cidofovir是一种无环核苷膦酸酯（ANP），该磷酸（ANP）被设计为抗HERPES病毒药物，用于治疗CMV视网膜炎，可用于治疗痘病毒感染。这项研究的目的是设计和合成比Cidofovir更有效和有选择性的ANP，可以口服给药，并且具有出色的安全性。我们将专注于两种结构类型的母体化合物，它们在体外表现为活性和体内针对痘病毒：（a）cidofovir的类似物和（b）HPMP-DAP的“开环”类似物。这些铅结构的修饰应导致具有增强抗Poxvirus活性和/或改善药理学参数的新型化合物。 Cidofovir的修饰将在胞嘧啶碱基（在N-4和C-5位置取代），而在“开环”系列修饰中，将主要集中于6-烷氧基链的改变，具有HPMP类型的结构性特征（Alkyl Chainot of Alkyl链的组合，磷氧基组和HYDROCT组的修饰），Hydroxy and hydrox and thydrox and。这些化合物将通过早期开发的ANP合成方法制备，并将评估其对各种痘病毒复制的抑制作用。具有出色安全性的化合物，并且在各种动物模型中，将评估与CIDOFOVIR相同或更有效的化合物。在这些动物模型中证明的化合物至少与Cidofovir一样有效，然后将成为详细的药理，药代动力学和毒理学研究的主题。另外，前药将准备允许口服后允许出色的活动。该应用的最终目标是推进治疗（全身或皮肤）痘病毒感染的化合物，即开发的初始阶段，即选择IND候选者。

项目成果

Inhibition of vaccinia virus replication by two small interfering RNAs targeting B1R and G7L genes and their synergistic combination with cidofovir.

两种针对 B1R 和 G7L 基因的小干扰 RNA 及其与西多福韦的协同组合抑制痘苗病毒复制。

• DOI: 10.1128/aac.01626-08
• 发表时间: 2009
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Vigne,Solenne;Duraffour,Sophie;Andrei,Graciela;Snoeck,Robert;Garin,Daniel;Crance,Jean-Marc
• 通讯作者: Crance,Jean-Marc

Antiviral activity of HPMPC (cidofovir) against orf virus infected lambs.

• DOI: 10.1016/j.antiviral.2006.09.008
• 发表时间: 2007-03
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: A. Scagliarini;Colin McInnes;L. Gallina;F. D. Pozzo;L. Scagliarini;R. Snoeck;S. Prosperi;J. Sales;J. Gilray;P. Nettleton