Abstract
As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein–protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide.
Highlights
Tumour necrosis factor alpha (TNFα) is a pleiotropic inflammatory cytokine produced and secreted mainly by macrophages, which can be produced by many other cells, for instance, CD4+ lymphocytes, neutrophils, NK cells and mast cells [1]
In an attempt to discover improved anti-TNFα therapeutics, we designed a cyclic peptide that could directly inhibit the TNFα-TNFR1 interaction and have potentially fewer side effects than the small molecule inhibitors and biologics mentioned above. This was achieved by producing a cyclic peptide with higher target specificity compared to small molecules and low potential of immunogenicity when compared with biologics
The cyclic peptide cyclo-GCRLYGFKIHGCG derived from the regulatory subunit (CK2β) of protein kinase 2 which inhibits the interaction with the associated catalytic subunit and is used for cancer therapy [21]
Summary
Tumour necrosis factor alpha (TNFα) is a pleiotropic inflammatory cytokine produced and secreted mainly by macrophages, which can be produced by many other cells, for instance, CD4+ lymphocytes, neutrophils, NK cells and mast cells [1]. Small molecule with anti-TNFα activity with compact 3D conformations containing trifluoromethylphenyl indole and chromone moieties have previously been designed These compounds bind with high affinity (IC50 = 13 μM) to a hydrophobic binding pocket formed by six tyrosine residues (Y59, Y119 and Y151 from chain A and B) at the interface of TNFα dimer [17]. A small molecule benzimidazole derivative (UCB-6876) has been discovered, a co-crystal structure of UCB-6876 with TNFα resulted in a change in the spatial arrangement of the TNFα trimer and a loss of its 3-fold symmetry This compound was found to occupy the centre of the TNFα trimer filling a hydrophobic binding pocket involving chain A (Y59), chain B (L57, Y119) and chain C (Y59, Y151) [19]
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