Catalytic Antibody-Based Vaccine For Weight Loss

描述（由申请人提供）：全球近10亿人超重或肥胖（体重指数，BMI，分别= 25- <30 and >30 kg/m2）。虽然超重和肥胖在富裕国家如美国很普遍，但在发展中国家如中国、印度和拉丁美洲却显著增加，这代表了一场全球公共卫生危机。事实上，在1980-2002年期间，成人（20岁以上）的肥胖患病率翻了一番，儿童和青少年（6-19岁）的肥胖患病率翻了三倍。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，与肥胖有关的死亡人数已上升到每年近30万人，估计经济成本为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开发基于最近发现的激素ghrelin的治疗体重增加的疗法，因为它具有刺激食欲和调节能量稳态的功能。我们的方法是双管齐下的，我们将开发催化抗体，专门作用于ghrelin和平行，我们将设计负责ghrelin的独特的翻译后修饰的酶的抑制剂。为此，我们将致力于以下几个方面的工作：（1）设计并化学合成能水解生长激素释放肽正辛酰基侧链的过渡态类似物（半抗原）。(2)我们将利用合成的半抗原免疫小鼠以产生单克隆抗体。(3)我们将表征每种催化抗体的动力学效率。(4)与催化抗体方法平行，我们还将使用过渡态理论来设计生长素O-酰基转移酶的抑制剂，该酶负责连接生长素的正辛酰基侧链。公共卫生相关性：超重和肥胖（体重指数，BMI，分别= 25- <30 and >30 kg/m2）是影响全球近10亿人的全球流行病。因此，已经投入了大量的努力来发现这些疾病的新疗法，包括手术和非手术疗法;然而，这些治疗往往只是姑息性的，并且只有在治疗继续时才有效。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，这种蛋白质可能与经常观察到的随后的体重反弹有关，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.