Targeted Drug Melts Fat in Obese Monkeys

During the past 20 years, there has been a dramatic increase in obesity in the United States and rates remain high. In 2010, no state in the United States had a prevalence of obesity less than 20%. Approximately one in three adults and one in six children are obese. Obesity is epidemic in the United States today and a major cause of death, attributable to heart disease, cancer, and diabetes.

Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Currently, only two Food and Drug Administration (FDA) approved drugs for weight loss are available in the United States: the appetite suppressant phentermine and the inhibitor of fat absorption orlistat. Orlistat (Xenical) is a weight-loss medication for long-term weight loss. This medication blocks the digestion and absorption of fat in your stomach and intestines. Other attempts to treat obesity have also predominantly focused on drugs aimed at suppressing appetite or increasing metabolism, but these efforts have been hampered by their toxic side-effects. Unfortunately, it’s common to regain weight no matter what obesity treatment methods you try.

In contrast, an MD Anderson group designed a new drug, the ligand-directed peptidomimetic CKGGRAKDC-GG-D(KLAKLAK)2 (termed adipotide), which is a synthetic peptide that triggers cell death. The drug acts on white adipose tissue. The white adipose tissue is the unhealthy type of fat that accumulates under the skin and around the abdomen.

In earlier preclinical research, obese mice lost about 30 percent of their body weight with this peptidomimetic peptide. Monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Overall and abdominal body fat levels drop, with reversible renal side effects Weight, BMI and abdominal circumference all continued to drop for three weeks after treatment ended before slowly beginning to reverse during the fourth week of the follow-up period. Monkeys in the studies demonstrated no signs of nausea or food avoidance. The renal effect was dose-dependent, predictable and reversible. This is a potentially important finding since unpleasant side-effects have limited the use of approved drugs that reduce fat absorption in the intestines.

Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans.

This is an alternative approach based on libraries of natural, highly structured peptides that offers new opportunities for identifying effective, specific inhibitors of protein-protein interactions. Peptide libraries constitute virtually all of the available classes of protein fold structures, providing a rich source of peptides that interact specifically and with high affinity to human proteins.

Using peptide library, the MD Anderson group is able to screen and identify those that bind to specific vascular cells among the many possible “ZIP codes” present in a human vascular map. This approach may help not only in understanding the implications of each interaction identified within the interactome but also in the development of effective drugs targeted to particular protein functions. Although peptide libraries are active in animal models, the challenge remains to demonstrate efficacy and safety in a clinical setting.

www.cdc.gov/CDCTV/ObesityEpidemic/

This video explains the many factors that have contributed to the obesity epidemic, and showcases several community initiatives taking place to prevent and reduce obesity. Obesity is a national epidemic and a major contributor to some of the leading causes of death in the U.S., including heart disease, stroke, diabetes and some types of cancer. We need to change our communities into places that strongly support healthy eating and active living.

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