Oral prodrug of a novel antiviral that blocks neuronal reactivation of HSV

描述（由申请人提供）：神经元的单纯疱疹病毒（HSV）潜伏感染没有“治愈”，并且无症状再激活和感染性病毒通过粘膜同时转移的可能性是当前疗法的显著缺点。我们开创了疱疹病毒特异性胸苷激酶（TK）的选择性抑制剂的研究，该酶负责抗疱疹核苷类似物的“激活”和从感觉神经节中的潜伏状态再激活病毒。然而，动物研究需要腹膜内给药测试化合物，因为这些化合物在水中溶解性差，并且不能充分口服以保证通过口服途径研究它们的有效性。在增强候选药物口服吸收的策略中，我们合成了两种有前途的化合物的6-脱氧类似物，并发现其中一种，我们称之为SacrovirTM，在小鼠中具有中等的口服吸收，通过与增溶聚合物Soluplus混合来增强，并几乎完全转化为最终药物N2-[m-（三氟甲基）苯基]鸟嘌呤，mCF 3 PG。因此，我们建议开发一种或多种制剂，其将大大增加Sacrovir的口服吸收并在HSV再活化的动物模型中显示口服功效。为实现这一目标，我们的具体目标是：1.配制前体药物Sacrovir（6-deoxy-mCF 3 PG）以增强其肠道吸收;策略包括乳剂、小分子佐剂和增溶剂; 2.通过用LC-MS方法分析前药和最终药物mCF 3 PG的血浆样品，比较Sacrovir制剂在小鼠中的口服生物利用度; 3.测定口服Sacrovir治疗后mCF 3 PG在兔和豚鼠中的口服生物利用度;和4）通过合作者测试口服Sacrovir在兔和豚鼠HSV再活化模型中的功效。在成功证明Sacrovir的最佳口服制剂后，将由分包商Dr. James M.希尔在路易斯安那州立大学健康科学中心，新奥尔良，和博士大卫伯恩斯坦和朗达卡丁的辛辛那提儿童医院医疗中心，根据合同从NIAID（博士石楠格林斯通，抗病毒分支）。积极的结果将作为背景，以确保额外的资金，例如通过第二阶段的小企业赠款，并最终从企业赞助商或持牌人，以充分开发药物。前体药物Sacrovir将代表神经元HSV潜伏感染的一流的新型口服治疗，重要的是，它将防止无症状的病毒脱落和由此产生的感染传播给性伴侣。 公共卫生相关性：单纯疱疹病毒感染没有“治愈”;病毒从神经元中的潜伏状态的无症状再活化及其通过粘膜的转移是当前疗法的显著缺点。我们已经合成了一种前体药物“SacrovirTM”，其在小鼠中口服吸收并代谢转化为最终的抗再活化药物“mCF 3 PG”。在这个项目中，我们将开发一种制剂，将增加其口服吸收在小鼠中，并表明，这种制剂将在兔和豚鼠模型的单纯疱疹病毒再激活的有效性。Sacrovir代表了一流的新型口服治疗潜伏性单纯疱疹病毒感染的神经元，重要的是， 传染性病毒的传播。

DESCRIPTION (provided by applicant): There is no "cure" for herpes simplex virus (HSV) latent infections of neurons, and the possibility of asymptomatic reactivation and simultaneous transfer of infectious virus via mucous membranes is a significant drawback of current therapies. We have pioneered the study of selective inhibitors of the herpes virus-specific thymidine kinase (TK), the enzyme responsible both for "activation" of anti-herpes nucleoside analogs and for reactivation of virus from the latent state in sensory nerve ganglia. Animal studies, however, have required intraperitoneal dosing of test compounds because the compounds are poorly soluble in water and not sufficiently orally available to warrant study of their effectiveness by the oral route. Among strategies to enhance oral absorption of candidate drugs, we have synthesized the 6-deoxy analogs of two promising compounds, and have found that one of these, which we call SacrovirTM, has moderate oral absorption in the mouse, which is enhanced by mixing with the solubilizing polymer Soluplus, and is converted nearly completely into the ultimate drug N2-[m-(trifluoromethyl) phenyl] guanine, mCF3PG. Thus, we propose to develop one or more formulations that will greatly increase the oral absorption of Sacrovir and show oral efficacy in animal models of HSV reactivation. To achieve this goal, our specific aims are to: 1. formulate the pro-drug Sacrovir (6-deoxy-mCF3PG) to enhance its intestinal absorption; strategies include emulsions, small molecule adjuvants, and solubility enhancers; 2. Compare oral bioavailability of Sacrovir formulations in the mouse, by analyzing plasma samples by LC-MS methods for both the pro-drug and the ultimate drug mCF3PG; 3. determine the oral bioavailability of mCF3PG in rabbits and guinea pigs after oral treatment with Sacrovir; and 4) test, through collaborators, the efficacy of oral Sacrovir in rabbit and guinea pi models of HSV reactivation. Following successful demonstration of an optimal oral formulation of Sacrovir, the experiments of aim 4 to test efficacy in rabbit and guinea pig models, respectively, will be conducted by subcontractor Dr. James M. Hill at LSU Health Sciences Center, New Orleans, and by Drs. David Bernstein and Rhonda Cardin of Cincinnati Children's Hospital Medical Center, under contract from NIAID (Dr. Heather Greenstone, Antiviral Branch). Positive results will be used as background to secure additional funding, for example through a phase II small business grant, and ultimately from a corporate sponsor or licensee, to fully develop the drug. The pro-drug Sacrovir will represent a first-in-class, novel oral treatment for HSV latent infections of neurons and, importantly, will prevent both asymptomatic virus shedding and the resulting transmission of infection to sex partners. PUBLIC HEALTH RELEVANCE: There is no "cure" for herpes simplex virus infections; asymptomatic reactivation of virus from the latent state in neurons and its transfer via mucous membranes is a significant drawback of current therapies. We have synthesized a pro-drug "SacrovirTM" that is both orally absorbed in mice and converted metabolically to the ultimate anti-reactivation drug, "mCF3PG". In this project we will develop a formulation of Sacrovir that will increase its oral absorption in mice, and show that this formulation will have efficacy in rabit and guinea pigs models of herpes simplex reactivation. Sacrovir represents a first-in-class, novel oral treatment for latent herpes simplex infections of neurons and, importantly, will prevent transmission of infectious virus.