Novel Target and Small Molecule Lead Discovery Against Drug Resistant HIV

艾滋病毒/艾滋病仍然是一个重大的全球公共卫生问题，面临着新出现的多重耐药的威胁 病毒株，因此这也是一个非常大的经济问题。2014年底，约有1 美国有100万艾滋病毒/艾滋病患者，全球有3690万人；新增加了200万人 2014年感染艾滋病。这种流行病继续蹂躏着甚至美国，约有5万人感染了新的艾滋病毒 每年都有感染。尽管有现代的联合疗法，艾滋病毒仍然是一个相当大的挑战和威胁。 因为耐多药菌株的数量迅速上升。对一种或多种药物联合耐药 是不可避免的。数百万患者的HIV毒株可以抵抗一种或多种目前可用的HIV 治疗。为了克服艾滋病毒的耐药性，迫切需要新的有效靶点和新的治疗方法 需要的。Sirga Advanced Biophma(Sirga Advanced Biophma)正在通过发现小分子来迎接这一挑战 中断人类细胞和病毒之间的相互作用的药物--这种相互作用绝对是 对病毒复制和繁殖至关重要。这种特别关键的互动也是Sirga 科学家们调查发现，这种病毒对出现抗药性具有抵抗力。通过相互作用， 宿主细胞和病毒蛋白被认为是相互作用的重要目标，宿主rna的相互作用。 除了Sirga之外，与病毒蛋白结合的病毒还没有被开发为新疗法的干预场所。 Sirga的初步研究项目已经非常成功地识别了三个小家庭 专门抑制艾滋病毒复制的分子，包括耐药菌株，细胞毒性低，在 非常初步的小鼠试验表明，每公斤体重的毫克没有毒性。在这个第一阶段的研究提案中， Sirga将把这些具有自己的衍生化学成分的热门化合物开发成有希望的先导化合物 新药发现。Sirga将从药理和结构上确定该药物的作用机制 多种推定药物，探索和优化生物活性小分子衍生物(结构/活性 关系)，几乎没有细胞和动物毒性。最有希望的化合物将被评估为 针对艾滋病毒耐药株的抗病毒药物。目标是开发出两到三个有希望的热门产品 通过破坏一种新的RNA/蛋白质功能将分子转化为治疗艾滋病毒/艾滋病的先导分子 被感染的细胞。这些目标的结果将是可衡量的。化合物AS的作用机理 新的病毒组装抑制剂将得到确认。Sirga将以令人信服的方式确定2到3个易处理的线索 高体外效力(≤1微米)，在NM范围内的细胞和 动物体内毫克/千克体重的范围。这些标准将与目前FDA批准的抗艾滋病毒药物几乎相当 并将使公司定位于提出第二阶段研究。

HIV/AIDS continues to be a major global public health issue with the threat of emerging, multi-drug resistant viral strains, and therefore it is also a very considerable economic issue. At the end of 2014 approximately 1 million people were living with HIV/AIDS in the US and 36.9 million people worldwide; 2 million became newly infected with AIDS in 2014. The epidemic continues to devastate even the US with some 50,000 new HIV infections each year. Despite modern combination therapies, HIV remains a considerable challenge and threat because of a rapid rise in multi-drug resistant strains. Resistance to one or more of the drugs in combination was inevitable. Millions of patients have strains of HIV that resist one or more of the currently available HIV therapies. To overcome HIV’s drug resistances, new validated targets and novel therapeutics are urgently needed. Sirga Advanced Biopharma (Sirga) is meeting this challenge with the discovery of small molecule drugs that interrupt an interaction between human cells and the virus - an interaction that is absolutely essential for viral replication and propagation. This particularly critical interaction is also one that Sirga scientists have investigated as being refractory to the emergence of drug resistance. Though interactions of host cell and viral proteins are the considered important targets of interaction, the interaction of the host RNA with viral proteins has not as yet been exploited as sites of intervention for new therapeutics, except by Sirga. Sirga’s initial research program has been extremely successful in identifying three families of the small molecules that specifically inhibit HIV replication including drug resistant strains, has low cell cytotoxicity and in very preliminary mouse testing indicated no-toxicity at mgs/kg body weight. In this Phase I research proposal, Sirga will develop these Hit compounds with its own derivative chemistries into promising Lead compounds for novel drug discovery. Sirga will determine the mechanism of action of the pharmacologically and structurally diverse putative drugs, and explore and optimize bioactive small molecule derivatives (Structure/Activity Relationships) with little to no cell and animal toxicity. The most promising of compounds will be assessed as antiviral agents against drug resistant strains of HIV. The goal is to develop two or three promising Hit molecules into Lead molecules for treating HIV/AIDS by disrupting a novel RNA/protein function found only in infected cells. The outcome of these Aims will be measureable. The mechanism of action of the compounds as novel inhibitors of viral assembly will be confirmed. Sirga will identify of 2 or 3 tractable Leads with convincing SAR, high in vitro potency (≤ 1 µM), and effective non-toxic concentrations in the nM range in cells and the range of mg/kg weight in animals. These criteria will be almost comparable to current FDA-approved anti-HIV drugs and will position the Company to propose Phase II research.