Bhattacharya Group: Developing novel therapeutics for inflammatory diseases
Our goals are to develop therapeutics targeting the chemokine network in inflammatory diseases affecting the heart, blood vessels and other organ systems.
Developing new therapeutics that target the chemokine network in inflammation is the major focus of our laboratory, which is based at the Wellcome Centre for Human Genetics.
Although inflammation is a fundamental host-defence response that serves to rid the body of the causes and consequences of infection and tissue injury, it is also a pathologic mechanism that can adversely affect organ function. Inflammation contributes to a variety of cardiovascular, pulmonary neurological, gastrointestinal, musculoskeletal, cutaneous, renal and hepatic disorders, creating substantial disease burden. Inflammation is driven by a network including secreted cytokines and chemokines, cellular receptors and leucocytes. The leucocytes include neutrophils, eosinophils, basophils, monocytes, macrophages, T and B-lymphocytes and dendritic cells. Cytokines and chemokines are secreted proteins, and are produced by damaged tissues in response to damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) which signal through pattern-recognition receptors to activate gene transcription. Chemokines cause directed leucocyte migration to sites of inflammation by signalling through cellular G-protein coupled receptors (GPCRs).
Despite having a well-documented mechanistic role in this process, and despite being supported by substantial target validation, no successful anti-chemokine therapeutic to treat inflammatory disease has yet been developed. We believe that the reason for this lies in the inherent robustness of the chemokine network. The robustness arises from the structure of the chemokine network. This includes large numbers of components (>40 chemokine, 19 GPCRs, multiple leucocyte subclasses), promiscuous interactions between chemokines and receptors, and promiscuous expression of GPCRs, which creates multiple synergistically acting pathways between chemokine and leucocytes. Leucocytes themselves are secrete multiple chemokines creating feedforward amplification, which also contributes to network robustness.
Ticks are blood-feeding parasites that parasitise mammals, birds, reptiles, and amphibians. They have adapted through evolution and natural selection for over 250 million years to evade the host's defence mechanisms, allowing them to feed for days to weeks. One class of proteins found in their saliva are called evasins. These bind and neutralise multiple chemokines, overcoming the robustness of the chemokine network, and inhibiting inflammation. Evasins have been shown to be potently active in several preclinical inflammatory disease models.
Using a biotechnology platform – Bug-to-Drug – that uses yeast surface display, we have identified and characterised over 40 evasins that have broad and promiscuous chemokine binding properties. As a result, they are predicted to be potently active in inflammatory diseases and have potential as biological therapeutics. We have improved on nature by combining these evasins to create “multi-warhead evasins” that extend their ability to block the chemokine network, and have shown that these are active in vivo. In ongoing work we are developing these novel evasins as biological therapeutics, and applying them in preclinical models of short-term inflammation, and in models of myocarditis and myocardial infarction.
BHF: We are supported by BHF Chair, BHF Program ("Precision Therapeutics for Cardiovascular Inflammation", BHF Project Grant ("Targeting the chemokine network in myocarditis using ligand traps derived from tick saliva"), BHF Centre of Research Excellence and BHF Centre for Regenerative Medicine Awards that fund our Bug to Drug, myocarditis and myocardial infarction work
MRC Confidence in Concept: Funding to develop 2-warhead evasins as therapeutic agents in myocarditis