University of Queensland researchers have developed series of novel, potent and selective, small organic molecules that mimic C3a (agonists) or inhibit its action (antagonists)
Diseases driven by chronic inflammation are major health burdens and controlling inflammation is an important preventative and therapeutic goal. A network of over 40 ‘Complement’ proteins is produced in blood and on cell surfaces in response to infection/injury. These proteins ‘complement’ immune cells and antibodies to identify, tag, destroy and eliminate pathogens and infected/damaged cells, and repair tissues. If the inflammatory stimulus is not removed by localized acute immune responses, complement activation can be prolonged or misdirected to healthy cells, and chronic inflammation can lead to inflammatory and autoimmune diseases.
Complement protein C3 is a central mediator of all avenues of complement activation leading to pathogen destruction and elimination. However, blocking C3 also blocks beneficial roles of complement cascade in fighting infection. A by-product of C3 cleavage to downstream immunological proteins is C3a, a 77-residue inflammatory protein that stimulates immune and metabolic responses. Its receptor (C3aR), a G-protein coupled receptor, is now thought to play important pathological roles in inflammatory and metabolic diseases and cancer, and its inhibition does not compromise immune defence but does dampen inflammatory responses. We have evidence that C3aR is a valuable anti-inflammatory drug target distinct from other complement components.
University of Queensland (UQ) researchers have developed multiple series of novel, potent and selective, small organic molecules that mimic C3a (agonists) or inhibit its action (antagonists). The team discovered how to downsize the native C3a protein to equipotent small molecule agonists and then switch agonists into antagonists.
Over 150 compounds have been identified as C3aR modulators in vitro, many with potent activity at nanomolar concentrations and selective binding to C3aR on human immune cells. None of the compounds bind at all to other complement proteins.
The UQ team has generated in vitro data showing functional activation (agonists) versus inhibition (antagonists) of mast cells, macrophages, neutrophils, dendritic cells, innate lymphoid cells. They identified signalling mechanisms responsible for some C3aR-mediated degranulation, chemotaxis, and cytokine secretion.
Selected compounds have been examined for stability in plasma and liver microsomes and have been shown to have efficacy in some C3aR-mediated rodent models of acute and chronic inflammatory conditions. For example, for proof-of-concept studies, C3aR agonists and antagonists have been profiled in neonatal and adult mouse models of lung inflammation and allergic asthma, comparing effects in C3aR knockout mice.
In a 17-day murine model of house dust mite (HDM) induced allergic asthma, challenge with an orally administered C3aR antagonist (10 mg/kg of A or B) on days 0 to 17 showed that antagonists A and B inhibited lung inflammation.
• Novel small molecule modulators of C3aR
• Potent and selective for human/mouse C3aR
• Orally active in inflammatory disease models
• Distinct ‘Complement’ target and mechanism of action
The compounds distinctly target the C3a receptor. The C3aR antagonists have potential as treatments for inflammation-related diseases where C3aR has been implicated as important through genetics, gene deletion in mice, or overexpression of C3a/C3aR , including:
• Asthma, allergies, respiratory diseases (e.g., lung inflammation, idiopathic pulmonary fibrosis, COPD)
• Arthritis, diseases of musculoskeletal system
• Metabolic Syndrome (including obesity, diabetes, cardiovascular disease)
• Inflammatory Bowel Disease (IBD), ulcerative colitis
• Autoimmune diseases (e.g., lupus, multiple sclerosis)
• Neurodegenerative diseases
• Nephritis and nephropathy
• Dermatological conditions (e.g., psoriasis, dermatomyositis)
• Transplant diseases and graft tolerance
• Stroke, ischemia/reperfusion injury
• Heart failure
• Cerebral arteriovenous malformations, aneurysmal subarachnoid hemorrhage
• Pregnancy issues, gestational diabetes, endometriosis
• Age-related macular degeneration
• Lyme disease
There is also potential to develop C3aR agonists for specific-immune related pathologies.