ALLOSTERIC MECHANISM FOR THE MODULATION OF G PROTEIN COUPLED RECEPTORS RELATED WITH PAIN AND OBESITY

G PROTEIN-COUPLED RECEPTORS (GPCRS) REGULATE A VAST AMOUNT OF CELLULAR PROCESSES, AND THEIR MALFUNCTION COMMONLY TRANSLATES INTO PATHOLOGICAL OUTCOMES. THUS, THEY FORM ONE OF THE MOST IMPORTANT PHARMACEUTICAL DRUG-TARGET CLASS (~34% OF ALL DRUGS APPROVED BY THE US FOOD AND DRUG ADMINISTRATION). HOWEVER, THESE DRUGS TARGET
THIS PROPOSAL ADDRESSES THE CHALLENGING TASK OF DEVELOPING NEW THERAPEUTIC STRATEGIES FOR GPCR MODULATION AND DISEASE TREATMENT. WE HAVE SELECTED TWO DISEASES OF EXTREME IMPORTANCE FOR THE QUALITY OF LIFE: PAIN AND OBESITY. MORE THAN 20% OF ADULTS WORLDWIDE EXPERIENCE DIFFERENT TYPES OF CHRONIC PAIN. SEVERAL APPROVED PAINKILLERS ARE AVAILABLE, BUT CURRENT ANALGESICS ARE OFTEN HAMPERED BY INSUFFICIENT EFFICACY AND/OR SEVERE ADVERSE EFFECTS (OPIOID CRISIS). SIMILARLY, OBESITY REPRESENTS A MAJOR HEALTH CHALLENGE BECAUSE IT INCREASES THE RISK OF DISEASES SUCH AS DIABETES, FATTY LIVER DISEASE, HYPERTENSION, STROKE, …, THEREBY CONTRIBUTING TO A DECLINE OF THE QUALITY OF LIFE.

THE NOVEL APPROACHES WE ARE GOING TO UNDERTAKE TAKES ADVANTAGE OF THE ALLOSTERIC PROPERTIES OF GPCRS. ALLOSTERISM IS THE PROCESS BY WHICH THE BINDING OR/AND FUNCTION OF AN ENDOGENOUS OR EXOGENOUS LIGAND AT ONE LOCATION (THE ORTHOSTERIC SITE) IS INFLUENCED BY THE BINDING OF ANOTHER LIGAND (ALLOSTERIC MODULATOR) OR PROTEIN (HOMO/HETERO DIMERIZATION) AT A TOPOGRAPHICALLY DISTINCT SITE (THE ALLOSTERIC SITE). GPCRS CAN ALSO ENGAGE PROTEIN-PROTEIN ALLOSTERIC INTERACTIONS AMONG THEM, BY FORMING COMPLEXES CONSTITUTED BY THE SAME (HOMO) OR DIFFERENT (HETERO) RECEPTOR PROTOMERS. DRUGS TARGETING A SPECIFIC HETEROMER CAN POTENTIALLY BE MORE EFFICIENT IN A PARTICULAR CELL TYPE, CELLULAR DOMAIN, OR DISEASE. HERE, WE AIM TO DEVELOP POSITIVE ALLOSTERIC MODULATORS OF GPCRS AND TO STUDY GPCR HETEROMERS RELATED WITH PAIN AND OBESITY. THE GOAL OF THE PROGRAM IS TO TRANSLATE THIS NOVEL BIOLOGICAL KNOWLEDGE INTO PRACTICAL APPLICATIONS IN THE FIELD OF PHARMACOLOGY AND DRUG DEVELOPMENT.