De-novo design of complementary (antisense) peptide mini-receptor inhibitor of interleukin 18 (IL-18).
Complementary (antisense) peptide mini-receptor inhibitors are complementary peptides designed to be receptor-surrogates that act by binding to selected surface features of biologically important proteins thereby inhibiting protein-cognate receptor interactions and subsequent biological effects. Previously, we described a complementary peptide mini-receptor inhibitor of interleukin-1beta (IL-1beta) that was designed to bind to an external surface loop (beta-bulge) of IL-1beta (Boraschi loop) clearly identified in the X-ray crystal structure of this cytokine. Here, we report the de-novo design and rational development of a complementary peptide mini-receptor inhibitor of cytokine interleukin-18 (IL-18), a protein for which there is no known X-ray crystal structure. Using sequence homology comparisons with IL-1beta, putative IL-18 surface loops are identified and used as a starting point for design, including a loop region 1 thought to be equivalent with the Boraschi loop of IL-1beta. Only loop region 1 complementary peptides are found to be promising leads as mini-receptor inhibitors of IL-18 but these are prevented from being properly successful owing to solubility problems. The application of "M-I pair mutagenesis" and inclusion of a C-terminal arginine residue are then sufficient to solve this problem and convert one lead peptide into a functional complementary peptide mini-receptor inhibitor of IL-18. This suggests that the biophysical and biological properties of complementary peptides can be improved in a rational and logical manner where appropriate, further strengthening the potential importance of complementary peptides as inhibitors of protein-protein interactions, even when X-ray crystal structural information is not readily available.
Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London SW7 2AZ, UK.
Ashish
A
Bhakoo
John G
JG
Raynes
Jonathan R
JR
Heal
Michael
M
Keller
Andrew D
AD
Miller
D015195:Drug Design; D006801:Humans; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D053727:Interleukin-18 Receptor alpha Subunit; D007700:Kinetics; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D018123:Receptors, Interleukin / Q000737:chemistry*; D053724:Receptors, Interleukin-18; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D010455:Peptides; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18