Multitarget-directed ligands (MTDLs) are hybrid ligands obtained by covalently linking active pharmacophores that can act on different targets. We envision that the concept of MTDLs can also be applied to supramolecular bioinorganic nanohybrid systems. Here, we report the inhibition of multimolecular RNA-protein complexes using multitarget-directed peptide-carbon nanotube hybrids (SPCHs). One of the most well-characterized and important RNA-protein interactions, a Rev-response element (RRE) RNA:Rev protein:Crm1 protein interaction system in human immunodeficiency virus type-1, was used as a model of multimolecular RNA-protein interactions. Although all previous studies have targeted only one of the interaction interfaces, that is, either the RRE:Rev interface or the RRE-Rev complex:Crm1 interface, we here have developed multitarget-directed SPCHs that could target both interfaces because the supramolecular nanosystem could be best suited for inhibiting multimolecular RNA-protein complexes that are characterized by large and complex molecular interfaces. The results showed that the single target-directed SPCHs were inhibitory to the single interface comprised only of RNA and protein in vitro, whereas multitarget-directed SPCHs were inhibitory to the multimolecular RNA-protein interfaces both in vitro and in cellulo. The MTDL nanohybrids represent a novel nanotherapeutic system that could be used to treat complex disease targets.
Keywords: multitarget-directed ligand; multivalency; peptide−CNT hybrid; scaffold-mediated peptide coassembly; supramolecular inhibitor.