Targeting virulence against oral candidiasis in HIV/AIDS

描述(申请人提供)：口腔症状被广泛认为是艾滋病毒感染和艾滋病自然病史和进展的重要标志。有趣的是，从很早的报道中就已经发现，口咽念珠菌病(OPC)或鹅口疮是定义艾滋病的机会性感染之一。即使在后HAART(高效抗逆转录病毒疗法)时代，OPC仍然是最常见的艾滋病定义疾病之一，也是艾滋病毒阳性患者最常见的机会性口腔感染。在HIV感染的患者中，机会致病真菌白色念珠菌是OPC发作的主要原因，因为这种原本正常的共生利用了潜在的免疫抑制。目前治疗OPC的抗真菌疗法有许多缺点，原因是抗真菌药物的数量有限，一些现有治疗方法显示出毒性，主要是对大多数类别的抗真菌药物出现耐药。由于传统的抗真菌药物针对的是对生长至关重要的过程，它们施加了高度的选择压力，耐药性的演变是不可避免的。事实上，所有临床使用的抗真菌药物都有抗药性的记录。靶向致病机制而不是关键过程是开发新抗生素的一个非常有吸引力的选择。口腔感染期间白色念珠菌的毒力与其进行形态发生等转化(丝状化)和形成生物膜的能力密切相关。因此，我们推测丝状化和生物被膜的形成是预防和治疗口腔念珠菌病的新的抗毒力方法的开发的高价值靶标，但在临床上尚未开发。我们已经进行了高含量的筛选，并确定了专门抑制白色念珠菌生物膜形成和丝状化的小分子化合物。本申请使用我们在这些筛选中确定的主导化合物--我们已经证实其缺乏毒性和体内有效活性--以充分验证丝状化和生物膜形成的抑制作为开发针对口腔念珠菌病的新的抗毒力方法的替代目标，为此，我们将i)进一步表征我们的先导抗毒力化合物的体外活性，重点是最小化诱导耐药性的可能性，ii)在口腔念珠菌病的小鼠模型中确定其体内活性，iii)确定在口腔念珠菌病期间用我们的先导化合物治疗宿主免疫反应的影响，从分子水平刻画其作用机理(-S)。

DESCRIPTION (provided by applicant): Oral manifestations are widely regarded as important markers of the natural history and progression HIV infection and AIDS. Interestingly, already from the very early reports, one of the AIDS-defining opportunistic infections was oropharyngeal candidiasis (OPC) or thrush. Even in the post-HAART (Highly Active Antiretroviral Therapy) era, OPC still remains one of the most common AIDS defining illnesses and the most common opportunistic oral infection in HIV positive individuals. In HIV-infected patients, the opportunistc pathogenic fungus C. albicans is responsible for the majority of OPC episodes, as this otherwise normal commensal takes advantage of the underlying immunesuppression. Current antifungal therapy for the treatment of OPC has many shortcomings, due to the limited armamentarium of antifungal agents, the toxicity displayed by some of the current therapies and, principally, the emergence of resistance to most classes of antifungals. As conventional antifungal agents target processes that are essential for growth, they impose a high degree of selective pressure and the evolution of resistance is unavoidable. Indeed, resistance has been documented for all clinically used antifungal agents. Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. C. albicans virulence during oral infection is intimately linked to its ability to undergo morphogenetc conversion (filamentation) and to form biofilms. Thus, we surmise that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches for the prevention and treatment of oral candidiasis. We have carried out high content screens and identified small molecule compounds that specifically inhibit C. albicans biofilm formation and filamentation. This application uses our leading compound identified during these screens - for which we have already confirmed lack of toxicity and potent in vivo activity - to fully validate inhibition of filamentation and biofilm formation as alternatie targets for the development of a novel anti-virulence approach against oral candidiasis, for which we will i) further characterize the in vitro activity of our lead anti-virulence compound, wih emphasis on minimizing the potential to induce resistance, ii) determine its in vivo activity in a mouse model of oral candidiasis, iii) determine the impact of treatment with our lead compound in the host immune responses during oral candidiasis, and iv) characterize its mechanism(- s) of action at the molecular level.