Targeting C-reactive protein using structure-guided drug design for therapeutic gain
Lead Research Organisation:
University of Bristol
Department Name: Biochemistry
Abstract
Our immune system protects us against invading pathogens and helps to clear up debris in our bodies. However, when our immune system is activated in the wrong place or at the wrong time, this can lead to autoimmune diseases, inflammation, and cardiovascular illnesses. Understanding how our immune system is activated will provide valuable insights into how we can control it, which will also allow us to treat diseases such as heart attacks, strokes, rheumatoid arthritis, lupus, and a variety of infections.
We have recently discovered that the shape of molecules called C-reactive protein (CRP) dictates how it functions. One CRP shape leads to aggregation of pathogens, aiding their clearance and destruction, whilst another shape leads to activation of part of our immune system called Complement. These two shapes are diametrically opposed, and so controlling the ability of CRP to form these shapes will allow us to control the function of CRP. We have developed molecules that can bind to and alter the ability of CRP to activate Complement and aggregate material, and with this grant we will investigate these as potential drugs to treat infections and autoimmune diseases.
We have recently discovered that the shape of molecules called C-reactive protein (CRP) dictates how it functions. One CRP shape leads to aggregation of pathogens, aiding their clearance and destruction, whilst another shape leads to activation of part of our immune system called Complement. These two shapes are diametrically opposed, and so controlling the ability of CRP to form these shapes will allow us to control the function of CRP. We have developed molecules that can bind to and alter the ability of CRP to activate Complement and aggregate material, and with this grant we will investigate these as potential drugs to treat infections and autoimmune diseases.
Technical Summary
C-reactive protein (CRP) is a protein of the innate immune system and a member of the pentraxin family. In humans, functions of CRP include mediating immune defence, inflammation and autoimmunity. CRP is also a target for therapeutic intervention. However, to date, no CRP-targeting have been successfully applied in the clinic. This dearth of therapeutics is partly a result of the lack of structural information regarding the pentraxin family, which limits our understanding of how they function.
We have recently developed a structure-determination pipeline for the pentraxins using cryo-electron microscopy (cryoEM), which revealed that CRP forms pentamers and decamers in solution, but 2D arrays on lipid membranes. These new structures revealed how CRP pentamers can reversibly assemble into different shapes, and it is these shapes that dictate their immunological function. Control of these shapes will therefore give us control of their function, which can be used to treat a variety of diseases.
We have various molecules that can selectively modulate the function of CRP. In this proposal, we will use cryoEM to discover the structure-function relationships of these molecules. This will provide drug candidates to control CRP activation, with potential use for treating cardiovascular diseases, autoimmune disorders and infections.
We have recently developed a structure-determination pipeline for the pentraxins using cryo-electron microscopy (cryoEM), which revealed that CRP forms pentamers and decamers in solution, but 2D arrays on lipid membranes. These new structures revealed how CRP pentamers can reversibly assemble into different shapes, and it is these shapes that dictate their immunological function. Control of these shapes will therefore give us control of their function, which can be used to treat a variety of diseases.
We have various molecules that can selectively modulate the function of CRP. In this proposal, we will use cryoEM to discover the structure-function relationships of these molecules. This will provide drug candidates to control CRP activation, with potential use for treating cardiovascular diseases, autoimmune disorders and infections.
