Exciting advances in GPCR-based drugs discovery for treating metabolic disease and future perspectives

ABSTRACT

Introduction: Current pharmacological therapies that target single receptors have limited efficacy for the treatment of diabetes and obesity. Novel approaches with hybrid peptides that activate more than one receptor at once to generate beneficial effects through synergistic effects have shown promising results. Several unimolecular dual and tri-agonists, mainly associated with GPCR like GLP-1/GCG/GIP receptors, have shown exceptional efficacy in preclinical models, and are currently being evaluated in clinical trials to investigate their safety and beneficial effects in humans.

Areas covered: Herein, the authors review the development of drugs used in the treatment of metabolic disease, from single agonists to the new generation of tri-agonist peptides and compile the latest knowledge available on GPCR-based drug discovery. The authors also provide the reader with their expert perspectives on this exciting area of drug development.

Expert opinion: The co-agonists that have been clinically tested so far have been well tolerated and reduce body weight as well as fasting glucose levels in patients with Type 2 Diabetes Mellitus to a higher degree than single agonists alone. The promising data collected so far now warrant large scale randomized clinical trials to assess whether a unimolecular polypharmacy-based approach could translate into safe and efficacious treatments for obesity and its comorbidities.

KEYWORDS:

• GPCRs
• GLP-1
• glucagon
• GIP
• unimolecular polypharmacy
• obesity
• T2DM

Article highlights

• GPCRs are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological advantages.

• GLP-1 receptor agonists effectively reduce weight and attenuate hyperglycemia and are currently a good example of successful GPCR-targeting drugs for treating obesity and/or type II diabetes.

• Preclinical studies indicate that pharmacological treatments of obesity targeting single receptors has limited efficacy relative to hybrid peptides that generate their beneficial effects through synergistic actions on several receptors.

• Several unimolecular dual-agonists associated to GPCRs have shown metabolic benefits in mice and non-human primates and many of them are currently evaluated successfully in clinical trials to investigate the safety and beneficial effects in humans.

• The success of the dual agonists has inspired research towards the generation of single molecules targeting three receptors, where those based on GPCRs have shown to be highly promising.

Declaration of interest

M. Quiñones is a recipient of a Postdoctoral contract from Galician Government (Xunta de Galicia ED481B2018/004). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work is supported by grants from the Ministerio de Economia y Competitividad (RN: BFU2015-70664R), the Xunta de Galicia (RN: 2015-CP080 and 2016-PG057), the Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and the European Community Seventh Framework Programme (RN: ERC-2011-StG-OBESITY53-281408). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds.