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.
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.
| Garner, Amanda L; Janda, Kim D (2011) Shedding light on the ghrelin/GOAT metabolism saga. Chembiochem 12:523-5 |
| Garner, Amanda L; Janda, Kim D (2011) Protein-protein interactions and cancer: targeting the central dogma. Curr Top Med Chem 11:258-80 |
| Garner, Amanda L; Janda, Kim D (2011) A small molecule antagonist of ghrelin O-acyltransferase (GOAT). Chem Commun (Camb) 47:7512-4 |
| Garner, Amanda L; Yu, Jing; Struss, Anjali Kumari et al. (2011) Synthesis of 'clickable' acylhomoserine lactone quorum sensing probes: unanticipated effects on mammalian cell activation. Bioorg Med Chem Lett 21:2702-5 |
| Garner, Amanda L; Janda, Kim D (2010) cat-ELCCA: a robust method to monitor the fatty acid acyltransferase activity of ghrelin O-acyltransferase (GOAT). Angew Chem Int Ed Engl 49:9630-4 |
| Gloeckner, Christian; Garner, Amanda L; Mersha, Fana et al. (2010) Repositioning of an existing drug for the neglected tropical disease Onchocerciasis. Proc Natl Acad Sci U S A 107:3424-9 |
