Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins

Abstract

The capsid of human immunodeficiency virus type 1 (HIV-1) is a shell that encloses viral RNA and is highly conserved among many strains of the virus. It forms a conical structure by assembling oligomers of capsid (CA) proteins. CA dysfunction is expected to be an important target of suppression of HIV-1 replication, and it is important to understand a new mechanism that could lead to the CA dysfunction. A drug targeting CA however, has not been developed to date. Hydrophobic interactions between two CA molecules via Trp184/Met185 in CA were recently reported to be important for stabilization of the multimeric structure of CA. In the present study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site, was synthesized and its significant anti-HIV-1 activity was confirmed. Structure activity relationship (SAR) studies of its derivatives were performed and provided results that are expected to be useful in the future design and development of novel anti-HIV agents targeting CA.

Rotten to the core: antivirals targeting the HIV-1 capsid core

“…A highly conserved Tryptophan (W)–Methionine (M) dipeptide (W184/M185) motif in H9 of CA CTD is engaged in hydrophobic interactions with the corresponding W184/M185 residues of a CA in a neighboring hexamer, at the twofold symmetry axis. Not surprisingly, mutations of these residues impair viral assembly [ 123 , 191 ]. A small molecule was selected by in silico screening as a peptidomimetic compound of W184/M185 in the interaction site.…”

“…Of note, the chirality of this molecule was important, as an MKN-1A diastereomer had decreased potency. Additionally, the trypsin-based indoyl and the methionine-based sulfidyl groups were essential for antiviral activity [ 191 ]. Hence, these efforts further confirmed that this site is a potential therapeutic target for subsequent drug design.…”

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins

“…This screening strategy provides some candidates with useful binding affinity, including MKN-1 (1) with a London dG value of −9.134, which had been found previously to have signicant anti-HIV activity. 75 This screening identied another candidate MKN-3 (2) with London dG value of −9.555, signifying a higher binding affinity for a CA molecule than that of MKN-1 (1). In the current study, MKN-3 (2) and several of its derivatives were synthesized, and their anti-HIV activity and cytotoxicity were evaluated.…”

“…Our strategy has involved design of small molecules, which might bind to the above site, using in silico screening. 75 Briey, a series of dipeptide mimics of Trp184 and Met185 were designed using the Molecular Operating Environment (MOE) (Chemical Computing Group Inc., Montreal, Quebec, Canada). The structure of one monomer molecule of the CA protein dimer (PDB ID: 3J34) remained as a receptor, and the backbone structure of Trp184 and Met185 of the other monomer molecule was removed.…”

Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies

“…The resistance of HIV to CA inhibitors requires mutations compromising the fitness of the virus, hence leading to a higher barrier to resistance and therapeutic efficiency. 10,11 So far, only a handful of capsid inhibitors are reported with benzodiazepine, 12 benzimidazole, 13 pyrrolopyrazolones, 14 furan, 15 and indole 16,17 scaffolds as in Fig. 1.…”