Inflammation, our bodies’ response to infection and injury, is generally regarded as a protective response that occurs to eliminate the offending stimulus and to promote repair and recovery. However, inflammation has a dark side. During chronic non-communicable diseases (such as diseases of aging like Alzheimer’s disease, vascular disease, even aging itself), inflammation is destructive.
The same inflammatory mechanisms that kill off infections start to attack our own healthy cells and make diseases worse. We think the reason for this may lie within a theory of evolution. Inflammation as a process is essential for the reproductive fitness of an organism. It is necessarily severe to combat potentially fatal infections. However, once we have ventured into our twilight years far beyond any reproductive activity the evolutionary pressures constraining inflammatory processes have gone, and so during diseases of aging, we are prone to suffer the ravaging effects of a maladaptive inflammatory response.
So how do we fix this? The simple answer is to use anti-inflammatory drugs. However, general anti-inflammatories could leave us dangerously susceptible to infection. We need to target specific components of the immune system to selectively target the damaging inflammation without affecting protective responses.
A multi-molecular protein complex called the NLRP3 inflammasome has been identified as an important regulator of maladaptive inflammatory responses in experimental models of disease. The NLRP3 inflammasome activates an enzyme called caspase-1. Caspase-1 is like a molecular pair of scissors that cuts inactive inflammatory signaling proteins (of the interleukin-1 family) into active molecules that then go one to drive devastating inflammatory responses.
Recent clinical trials targeting interleukin-1 directly have had very positive results in stopping the adverse effects of inflammation, and so the NLRP3 inflammasome is considered an important target for developing new drugs. As yet, however, there are no drugs available clinically that inhibit the NLRP3 inflammasome. We recently reported that some existing drugs could be repurposed, and there are some other successes. However, the number of new drug candidates coming through the pipeline has been relatively limited.
We recently published our attempts to provide a solution to inhibiting NLRP3. We discovered a new chemical motif, the oxazaborine ring, that endowed molecules with the property of potently inhibiting activation of the NLRP3 inflammasome. Through screening and rational chemical, design approaches with iterative assays of activity in biological models we evolved molecules from being weak inhibitors into potent inhibitors of the NLRP3 inflammasome.
Following multiple experimental rounds, we eventually ended up with a molecule 100 times more potent than our starting point. Importantly, we also removed potentially damaging off-target effects from early iterations of these molecules. We also demonstrated that these molecules were effective in in vivo models of inflammation highlighting their value as experimental tools and potential new analogs for drug development.
Thus we can now offer the field new chemical space to explore in the development of effective inhibitors, and potentially a new scaffold upon which new drugs can be built. Maybe we have opened a door.