Accelerating the Search for Novel Drugs
As a nonprofit research institute, we reinvest our net revenues in our programs, our people, and in investigator-led research projects in many areas. Among our FY2011 investments is a program to study a new molecular target that may prove to be useful in the treatment of heart disease, hypertension, diabetes, and a range of other disorders.
This research focuses on a recently discovered receptor known as APJ. The APJ receptor binds apelin, a peptide produced in the heart, liver, kidney, brain, and other organs. Among its many functions in the body, apelin lowers blood pressure, improves heart function, and appears to protect against nerve degeneration.
Led by research pharmacologist Rangan Maitra, PhD, senior research chemist Scott Runyon, PhD, and senior computational scientist Danni Harris, PhD, our multidisciplinary team is gaining a better understanding of the physiological functions of the APJ receptor by developing novel drugs that regulate its function.
The RTI team developed a simple, rapid, and robust in vitro assay to identify compounds that either activate or inhibit the apelin receptor. This assay enabled RTI researchers to identify early lead compounds and study various peptide fragments to better understand how these compounds bind to and activate the APJ receptor.
"Peptides like apelin are not themselves effective drugs because they are degraded too quickly by the body," explained Runyon. "The goal of our research is to accelerate the search for more metabolically stable compounds that bind to this receptor and therefore have therapeutic potential."
To facilitate this work, RTI developed a computer-aided drug design that identified a small motif of amino acids critical for receptor recognition and function. Simultaneously, the team synthesized small molecules that activate the receptor at very low concentrations and began work to refine these compounds to produce drug-like molecules for translational research.
We also undertook research to identify areas of unmet need where APJ ligands would be useful. In collaboration with scientists from Harvard University, we performed an epidemiological evaluation of apelin peptide levels in the blood of pregnant women with or without preeclampsia.
"Our pilot data suggest that lower levels of circulating apelin peptides are associated with preeclampsia," said Maitra.
We are continuing to explore other areas where compounds targeting APJ could be useful, such as HIV-induced neurodegeneration, liver disease, and diabetes.