A2A AR Agonists as Adjunct Therapy Against S. aureus Sepsis

描述(由申请人提供)：这是一项第一阶段的STTR申请，旨在研究腺苷治疗(ATL)实验室开发的选择性腺苷A2A受体(A2AR)激动剂在革兰氏阳性细菌脓毒症模型中的疗效，该研究将在传染病领域专家迈克尔·谢尔德博士的弗吉尼亚大学(UVA)实验室进行。脓毒症综合征是美国第11大主要死亡原因。每年发生近90万例，导致21万人死亡，其中50%的败血症病例是由金黄色葡萄球菌等革兰氏阴性病原体引起的。虽然已经尝试了许多针对炎症级联反应的新疗法，但结果总体上令人失望。我们推测，在脓毒症综合征发生后，选择性腺苷A2A受体(A2AR)激动剂通过灭活炎性造血细胞(中性粒细胞、单核细胞、巨噬细胞和T细胞)来保护组织免受组织损伤和炎症的有害影响。这导致中性粒细胞与内皮细胞的相互作用减少，从而消除了早期促炎细胞因子释放的级联反应，加剧了抗炎细胞因子-趋化因子反应。我们将具体评估1)3种新的、高选择性和有效的A2AR激动剂的药代动力学和配方稳定性；2)在金黄色葡萄球菌致死的脓毒症小鼠模型中评估这些化合物；以及3)评估对照和药物治疗动物的细胞因子谱，以更好地了解脓毒症的潜在机制和信号分子。这些目标与国家过敏和传染病研究所的使命直接相关，该研究所的使命是进行和支持基础和应用研究，以更好地了解、治疗并最终预防传染病、免疫学和过敏性疾病，目标是针对革兰氏阳性败血症的药物开发，目前的治疗方法对患者的护理和生存并不理想。

DESCRIPTION (provided by applicant): This is a phase I STTR application to study the efficacy of selective adenosine A2A receptor (A2AR) agonists developed in the laboratories of Adenosine Therapeutics (ATL) in models of Gram-positive bacterial sepsis which will be conducted in the University of Virginia (UVA) laboratories of Dr. Michael Scheld, an expert in the field of infectious disease. Sepsis syndrome is the 11th leading cause of death in the United States. Nearly 900,000 cases occur annually, resulting in 210,000 deaths, with 50% of sepsis cases due to Gram-negative pathogens such as S. aureus. While many new therapies targeting aspects of the inflammatory cascade have been tried, the results have been generally disappointing. We hypothesize that following the initiation of sepsis syndrome, selective adenosine A2A receptor (A2AR) agonists afford protection from tissue injury and the deleterious effects of inflammation by inactivating inflammatory hematopoeitic cells (neutrophils, monocytes, macrophages and T cells). This results in reduced neutrophil-endothelial cell interactions, thus abrogating the early cascade of pro-inflammatory cytokine release with an accentuation of an anti-inflammatory cytokine-chemokine response. We will specifically evaluate 1) the pharmacokinetics and formulation stability of 3 new, highly selective and potent A2AR agonists; 2) evaluate these compounds in a lethal murine model of sepsis using S. aureus; and 3) evaluate the cytokine profile of control and drug-treated animals to gain greater understanding of underlying mechanisms and signaling molecules in sepsis. These objectives directly relate to the mission of the National Institute of Allergy and Infectious Diseases, which is to conduct and support basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases, by targeting drug development for gram-positive sepsis, for which current therapies are not ideal for patient care and survival.