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Volume 3, Issue 2
ISSN: 2470-9905
Crystallography 2017
October 16-17, 2017
2
nd
International Conference on
October 16-17, 2017 | Chicago, USA
Applied Crystallography
Structure-based design of IL-17 antagonists
Shenping Liu
Pfizer Inc., USA
S
tatement of the Problem: IL-17A is a pro-inflammatory cytokine that is implicated in many autoimmune and inflammatory
diseases. Disruption of interactions between IL-17A and its main receptor, IL-17RA may be effective in treating these diseases.
Monoclonal antibodies targeting pathway of IL-17A have shown significant efficacies in treating psoriasis and psoriatic arthritis over
existing therapies. To develop non-antibody IL-17A antagonists, structure information of IL-17A, its complex with IL-17RA and
inhibitors are valuable. To develop non-antibody based IL-17A antagonists, we identify peptides, small molecules and fragment leads
through various techniques. We designed and produced well behaved IL-17A and IL-17RA, and obtained crystal structures of IL-17A
and IL-17RA. These structures provide the structural basis for IL-17A signaling through IL-17RA. We then move on to determine
the structures of IL-17A in complex with peptide and small molecule antagonists. Since both peptide and small molecules disrupt
the native structure of IL-17A and hinder crystallization, to achieve these structures we used FAB of an IL-17A targeting antibody as
a crystallization chaperon to stabilize IL-17A/peptide and IL-17A small molecule complexes. Furthermore, we conducted fragment
screen using large numbers of high diffracting apo IL-17A crystals, and identified two binders. These structures enabled us to
understand the structural basis of IL-17A signaling, identify lead materials and design IL-17A antagonists with much improved
potencies.
shenping.liu@pfizer.comStruct Chem Crystallogr Commun, 3:2
DOI: 10.21767/2470-9905-C1-003