Catalytic Antibody-Based Vaccine For Weight Loss

描述(申请人提供)：全球有近10亿人超重或肥胖(身体质量指数，BMI分别为25-30和30公斤/平方米)。虽然超重和肥胖在美国等富裕国家很普遍，但在中国、印度和拉丁美洲等发展中国家，超重和肥胖正在显著上升，这代表着一场全球公共卫生危机。事实上，在1980-2002年间，成年人(20岁以上)的肥胖率翻了一番，儿童和青少年(6-19岁)的肥胖率增加了两倍。超重和肥胖通常与许多疾病有关，如心脏病、某些癌症、2型糖尿病、中风、关节炎、呼吸问题和心理障碍。因此，与肥胖相关的死亡人数已上升至每年近30万人，估计经济损失为1170亿美元。因此，开发新的治疗方法对于阻止这一全球流行病至关重要。我们研究计划的长期目标是在最近发现的激素Ghrelin的基础上开发治疗体重增加的疗法，因为它具有刺激食欲和调节能量平衡的功能。我们的方法是双管齐下的，我们将开发专门作用于ghrelin的催化抗体，同时我们将设计负责ghrelin独特的翻译后修饰的酶的抑制剂。为此，我们将致力于以下目标：(1)设计并化学合成Ghrelin正辛酰基侧链的过渡态类似物(半抗原)。(2)利用人工合成的半抗原免疫小鼠，制备单抗。(3)我们将对每种催化抗体的动力学效率进行表征。(4)与催化抗体方法并行，我们还将利用过渡态理论设计Ghrelin O-酰基转移酶的抑制剂，Ghrelin O-酰基转移酶是负责连接Ghrelin的正辛酰基侧链的酶。公共卫生相关性：超重和肥胖(身体质量指数分别为25和30公斤/平方米)是影响全球近10亿人的全球性流行病。因此，已经投入了大量的精力来发现针对这些疾病的新的手术和非手术治疗方法；然而，这些治疗通常只有在继续治疗的情况下才是姑息和有效的。我们建议通过靶向一种已知在节食后增加的蛋白质来开发体重增加的治疗方法，这种蛋白质可能与随后经常观察到的体重恢复有关，这将改变肥胖治疗的范式。

DESCRIPTION (provided by applicant): Nearly 1 billion people worldwide are overweight or obese (body mass index, BMI, = 25-<30 and >30 kg/m2, respectively). Although prevalent in affluent nations such as the United States, overweight and obesity is significantly on the rise in developing nations such as China, India and Latin America representing a global public health crisis. In fact, between 1980-2002 obesity prevalence doubled in adults (age 20+ years) and tripled in children and adolescents (age 6-19 years). Overweight and obesity are commonly linked with many diseases such as heart disease, certain cancers, type 2 diabetes, stroke, arthritis, breathing problems and psychological disorders. As a result, deaths associated with obesity have risen to nearly 300,000 per year and the estimated economic cost is $117 billion. Thus, the development of new treatments is crucial in stopping this worldwide epidemic. The long-term goal of our research program is to develop therapies for the treatment of weight gain based on the recently discovered hormone, ghrelin, due to its function in stimulating appetite and regulating energy homeostasis. Our approach is two-prong in that we will develop catalytic antibodies that specifically act on ghrelin and in parallel we will design inhibitors of the enzyme responsible for ghrelin's unique posttranslational modification. Toward this goal, we will pursue the following aims: (1) We will design and chemically synthesize transition state analogs (haptens) for the hydrolysis of ghrelin's n-octanoyl side chain. (2) We will utilize the synthesized haptens for the immunization of mice to generate monoclonal antibodies. (3) We will characterize each catalytic antibody for its kinetic efficiency. (4) In parallel with the catalytic antibody approach, we will also use transition state theory to design inhibitors of ghrelin O-acyltransferase, which is the enzyme responsible for attaching ghrelin's n-octanoyl side chain. PUBLIC HEALTH RELEVANCE: Overweight and obesity (body mass index, BMI, = 25-<30 and >30 kg/m2, respectively) are global epidemics affecting nearly 1 billion people worldwide. As such, much effort has been invested in discovering new therapies, both surgical and nonsurgical, for these disorders; however, these treatments are often only palliative and effective only while treatment is continued. We propose to develop therapies for weight gain by targeting a protein known to be increased after dieting and potentially implicated in the subsequent weight regain often observed, which will change the paradigm of obesity therapy.