9y6c
X-ray structure analysis of human Complement Component 5 TE domain in complex with the peptide Ra30303
Structural highlights
DiseaseCO5_HUMAN Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:609536. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Note=An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele (PubMed:15995705). FunctionCO5_HUMAN Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled. Derived from proteolytic degradation of complement C5, C5 anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. C5a also stimulates the locomotion of polymorphonuclear leukocytes (chemokinesis) and direct their migration toward sites of inflammation (chemotaxis). Publication Abstract from PubMedComplement component 5 (C5) is a protein in the complement cascade and a part of the innate immune system that has been clinically validated as a therapeutic target for several immune-mediated diseases including generalized myasthenia gravis (gMG). In this paper, we discuss the early discovery of zilucoplan, a macrocyclic peptide drug, which was identified via innovative extreme diversity mRNA display (Ma, Z.; Hartman, M. C. T. In Vitro Selection of Unnatural Cyclic Peptide Libraries via mRNA Display. In Ribosome Display and Related Technologies: Methods and Protocols; Douthwaite, J. A., Jackson, R. H., Eds.; Springer: New York, 2012; pp 367-390.) against C5 and approved for the treatment of gMG. We highlight the key steps and rationale behind the peptide medicinal chemistry optimization of the initial screening hits, that led to improved potency, stability, and pharmacokinetic properties. Discovery of Zilucoplan: A Complement C5 Inhibitor for Treatment of Anti-Acetylcholine Receptor (AChR) Antibody-Positive Generalized Myasthenia Gravis (gMG).,Ye P, Hammer RP, Wang Z, Dhamnaskar K, Hoarty M, Ma Z, Tang GQ, DeMarco SJ, Ricardo A J Med Chem. 2025 Dec 11. doi: 10.1021/acs.jmedchem.5c02537. PMID:41379101[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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