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

描述（由申请人提供）：对于神经元的单纯疱疹病毒（HSV）潜伏感染没有“治愈”的方法，并且感染性病毒通过粘膜无症状再激活和同时转移的可能性是当前治疗的一个显著缺点。我们率先研究了疱疹病毒特异性胸苷激酶（TK）的选择性抑制剂，这种酶既负责“激活”抗疱疹核苷类似物，也负责从感觉神经节的潜伏状态重新激活病毒。然而，动物研究需要腹腔内给药试验化合物，因为这些化合物难溶于水，而且不能充分口服以保证通过口服途径研究其有效性。在增强候选药物口服吸收的策略中，我们已经合成了两种有前景的化合物的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，通过与增溶性聚合物Soluplus混合增强，并几乎完全转化为最终药物N2-[m-（三氟甲基）苯基]鸟嘌呤mCF3PG。因此，我们建议开发一种或多种制剂，这些制剂将大大增加Sacrovir的口服吸收，并在HSV再激活的动物模型中显示口服疗效。为实现这一目标，我们的具体目标是：1。配制前药Sacrovir (6-deoxy-mCF3PG)，促进肠道吸收；策略包括乳剂、小分子佐剂和溶解度增强剂；2. 通过LC-MS法分析血浆样品的前药和终药mCF3PG，比较萨罗韦制剂在小鼠体内的口服生物利用度；3. 测定口服Sacrovir后mCF3PG在家兔和豚鼠体内的生物利用度；4)通过合作者测试口服萨罗韦在兔和豚鼠HSV再激活模型中的效果。在萨罗韦最佳口服配方的成功演示之后，目标4的实验将分别在兔子和豚鼠模型中测试功效，将由分包商新奥尔良路易斯安那州立大学健康科学中心的James M. Hill博士和dr。辛辛那提儿童医院医疗中心的David Bernstein和Rhonda Cardin，根据NIAID （Heather Greenstone博士，抗病毒部门）的合同。积极的结果将作为获得额外资金的背景，例如通过第二阶段小企业赠款，并最终从企业赞助商或被许可方获得资金，以充分开发该药物。前药Sacrovir将代表一种一流的新型口服治疗HSV潜伏性神经元感染，重要的是，它将防止无症状病毒脱落和由此导致的感染传播给性伴侣。

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.