Resolution of inflammation: an emerging concept for the treatment of cardiovascular disease
Cardiovascular diseases are the number-one killer globally, as an estimated 18 million people died from cardiovascular diseases in 2016, representing 31% of all deaths globally. Cardiovascular diseases are a group of disorders affecting the blood vessels and heart.
Cardiovascular disease is increasingly recognised as a low-grade chronic inflammatory disorder. As such, inflammation plays a key role in the development and progression of many cardiovascular diseases, including high blood pressure (hypertension) and heart attack. Thus, developing novel therapeutic strategies to promote the resolution of inflammation is particularly attractive. The healthy inflammatory response is characterised by distinct phases; beginning with initiation and followed by resolution. During cardiovascular disease however, ‘chronification’ of inflammation occurs, resulting in a failure of the resolution of inflammation. It is essential to switch this chronic inflammation to the resolution phase to restore tissue homeostasis. Chronification of inflammation and the failure of inflammation resolution leads to chronic inflammatory state which promotes excessive tissue damage (see Figure above).
GPCR targets for the resolution of inflammation
We have revealed that anti-inflammatory proteins, called formyl-peptide-receptors (FPRs), play an important role in the development and progression of cardiovascular diseases, this reveals a previously unrecognised and novel therapeutic target. FPRs are members of the seven-transmembrane domain G-protein coupled receptor (GPCR) family, and are involved in the regulation and importantly, the resolution of inflammation. There are 3 FPRs which have been identified in humans; FPR1, FPR2 and FPR3, and are widely distributed throughout the human body, in various different cell types, but the actions of activating these receptors can be both beneficial and detrimental to the resolution of inflammation.
Excitingly, we have discovered the first evidence of the untapped therapeutic potential of FPRs in cardiovascular disease. We have demonstrated that our specially developed drugs called “biased-agonists” may provide a revolutionary strategy to treat cardiovascular disease. This approach of teaching receptor proteins in the heart and blood vessels a “new trick” to selectively activate desirable signalling pathways inside the cell, without triggering potentially detrimental signals (see Figure below), that could otherwise contribute to side-effects is an emerging concept to treat cardiovascular disease.
Biased-agonists offer the unique ability to target FPRs and favour their signalling away from detrimental mechanisms, to reduce side effects and provide a superior methods of FPR activation compared to conventional ‘unbiased’ means of activating such receptors. These observations provided powerful impetus for the development of biased, small-molecule FPR-activators as a novel medicine to treat heart attack. Our discovery of this novel platform was published in the prestigious scientific journal, Nature Communications, and the technology has been patented. We anticipate that our research has high translational potential and will ultimately facilitate the development of exciting new ways to treat the world’s leading of cause of death, cardiovascular disease.
Current Research Projects:
A novel anti-inflammatory approach to treat hypertension
Hypertension affects approximately 1 in 3 people worldwide and is a major contributor to acute life-threatening cardiovascular events such as heart attack and stroke. Importantly, as many of 12-30% of hypertensive patients are estimated to be resistant to currently available drug therapies, thus developing novel pharmacological therapeutic approaches are essential to address these shortcomings. Despite current knowledge that the immune system plays an important role in the progression of hypertension, and associated end-organ damage, this therapeutic avenue remains under-explored. Thus, targeting the FPR family, which is integral to the resolution of inflammation, may offer a new therapeutic approach to attenuate elevated blood pressure whilst simultaneously tempering the associated detrimental inflammatory state.
This project will extend from cell-based studies into well validated pre-clinical models of hypertension. The project will test the hypothesis that our prototype drug candidate will improve vascular function and protect against vascular injury in hypertension. We will examine the ability of our biased FPR activator to lower blood pressure, and limit consequential blood vessel inflammation and remodelling. The proposed studies will provide critical insight into the therapeutic potential of biased FPR agonists in hypertensive disease. We anticipate that this study will ultimately facilitate the development of exciting new ways to treat hypertension, a clinical syndrome that affects up to 25% of the global population.
A novel anti-inflammatory approach to treat pulmonary hypertension
Increased pressure within the blood vessels of the lungs (pulmonary hypertension) is a serious, frequently fatal disease that lacks an effective treatment. This cardiopulmonary disease has an unacceptably low survival rate, commonly less than 5 years following diagnosis as patients quickly die from right-sided heart failure. Currently available drugs only slightly improve symptoms, but do not offer a cure. This highlights pulmonary hypertension as a clear unmet clinical need, and innovative treatment strategies are urgently required for this devastating disease.
We have discovered an attractive and previously unrecognised approach using biased FPR agonist drugs to simultaneously lower blood pressure in the lungs, and reduce the stiffness of the blood vessels. This strategy could help keep the lung blood pressure down and also reverse some of the underlying damage. This project will test the hypothesis that biased FPR agonists will reverse impaired vascular function and protect against vascular injury in pulmonary hypertension-induced inflammation, fibrosis and remodelling. The proposed studies will provide insight into the therapeutic potential of biased FPR agonists, from pulmonary vascular cells in vitro to the whole animal in vivo. We anticipate that our research will ultimately facilitate the development of exciting new ways to treat this devastating disease.
FPR based rational drug design and molecular pharmacology
FPRs represent an attractive druggable target for cardiovascular diseases. Development of a novel molecule has been challenged by the metabolic instability of endogenous ligands, thus development of small-molecule FPR agonists, with better efficacy and fewer side-effects, may have significant translational and commercial value.
In this project, an iterative drug design process paired with medicinal chemistry and biological readouts, will profile beneficial vs detrimental signalling pathways of lead candidate molecules.This will enable us to further understand the molecular pharmacology of FPRs. This multidisciplinary project leverages the well-established GPCR screening algorithm and optimisation program which could lead to the discovery of potentially ground-breaking novel molecules to modulate FPR signalling. This exciting FPR research and development program aims to facilitate the development of superior drug candidates that will meet specific criteria to advance into clinical development, ready for early-phase clinical trials.