Mapping, Structure and Modulation of PPI

Abstract

Because of the key relevance of protein-protein interactions (PPI) in diseases, the modulation of protein-protein complexes is of relevant clinical significance. The successful design of binding compounds modulating PPI requires a detailed knowledge of the involved protein-protein system at molecular level, and investigation of the structural motifs that drive the association of the proteins at the recognition interface. These elements represent hot spots of the protein binding free energy, define the complex lifetime and possible modulation strategies. Here, we review the advanced technologies used to map the PPI involved in human diseases, to investigate the structure-function features of protein complexes, and to discover effective ligands that modulate the PPI for therapeutic intervention.

Keywords: PPI in disease1; ligand interaction5; modulation strategies3; protein-protein4; target structure2.

FIGURE 1

Selection of modulators targeting PPI (A) Structure of PEX14 bound the inhibitor [1-(2-hydroxyethyl)-5-[(4-methoxynaphthalen-1-yl)methyl]-∼(N)-(phenylmethyl)-6,7-dihydro-4∼(H)-pyrazolo (4,3-c)pyridine-3-carboxamide) that efficiently disrupts the PEX14-PEX5 interaction to treat trypanosomiases (Dawidowski et al., 2017) (B) Structure of human DNA polymerase processivity factor UL44 in complex with the covalent allosteric inhibitor {(5-[(dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo (c) thiophen-4(5H)-one]} that blocks the UL44-UL54 peptide interactions to treat human cytomegalovirus infections (Chen et al., 2017) (C) Structure of human TNFα in complex with the inhibitor JNJ525 {(N)4-(phenylmethyl)-∼(N)4-{2-[3-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]phenyl}pyrimidine-2,4-diamine} that blocks the TNF-TNFR1 signaling stabilizing a distorted TNFα complex (McMillan et al., 2021) (D) Structure of human Transthyretin in complex with the ligand Tafamidis [2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid] a potent and selective stabilizer that inhibits the amyloid cascade for the treatment of amyloid cardiomyopathy (Maurer et al., 2018) (E) Structure of the WD repeat domain five in complex with the macrocyclic peptidomimetic MM-589 {N-[(3R,6S,9S,12R)-6-ethyl-12-methyl-9-[3-(N′-methylcarbamimidamido)propyl]-2,5,8,11-tetraoxo-3-phenyl-1,4,7,10-tetraazacyclotetradecan-12-yl]-2-methyl propanamide} that blocks the WDR5-mixed lineage leukemia (MLL) protein-protein interaction (Karatas et al., 2017) (F) Structure of the anthrax toxin prepore in complex with the neutralizing Fab portion of the antibody cAb29 (Hoelzgen et al., 2021).