Poster Presentation First Malaria World Congress 2018

NMR reveals conformational properties of the Circumsporozoite protein central repeats (#455)

Chris MacRaild 1
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia

Antibodies targeting the central NANP/NVDP repeats of Circumsporozoite protein (CSP) appear to contribute to the protective effects of several experimental malaria vaccines, including RTS,S and PfSPZ. Recent structures have revealed details of how these antibodies recognise these repeats, and of the diversity of conformations adopted by the repeats when they are bound to antibodies. In order to make best use of this new structural information in the design of better CSP-based immunogens, it is necessary to consider the conformational properties of the repeats in the absence of antibody, but in the context of the full-length protein. Data addressing this question is currently lacking. We will present preliminary results from an NMR study of the conformations adopted by the NANP repeats in the context of full-length recombinant CSP. Our data show that the NANP repeats are highly flexible, but are remarkably homogeneous in average conformation, probably reflecting rapid conversion between multiple conformational states. There is some evidence to suggest that the specific conformations recognised by several antibodies are also sampled in the free protein. Stabilising these conformations may provide a strategy for the design of better immunogens. There is also some evidence that the conformational properties of the NVDP repeats may differ from the NANP repeats, an observation that may have implications for strategies to preferentially target the newly discovered junctional epitope in CSP.