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

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.

Potent leads based on CA-19L, an anti-HIV active HIV-1 capsid fragment.

Several anti-HIV-1 peptides have previously been found among overlapping fragment peptide libraries that contain an octa-arginyl moiety and cover the whole sequence of an HIV-1 capsid (CA) protein. Several derivatives based on a potent CA fragment peptide CA-19L have been synthesized. CA-19L overlaps with the Helix 9 region of the CA protein, which could be important for oligomerization of the CA proteins. Derivatives of CA-19L in which several amino acid residues were added to the N- and C-termini according to the natural CA sequence, were synthesized and their anti-HIV activity was evaluated. Some potent compounds were found, and these potential new anti-HIV agents are expected to be useful as new tools for elucidation of CA functions.

Exploratory studies on CA-15L, an anti-HIV active HIV-1 capsid fragment.

Utilizing overlapping fragment peptide libraries covering the whole sequence of an HIV-1 capsid (CA) protein with the addition of an octa-arginyl moiety, we had previously found several peptides with anti-HIV-1 activity. Herein, among these potent CA fragment peptides, CA-15L was examined because this peptide sequence overlaps with Helix 7, a helix region of the CA protein, which may be important for oligomerization of the CA proteins. A CA-15L surrogate with hydrophilic residues, and its derivatives, in which amino acid sequences are shifted toward the C-terminus by one or more residues, were synthesized and their anti-HIV activity was evaluated. In addition, its derivatives with substitution for the Ser149 residue were synthesized and their anti-HIV activity was evaluated because Ser149 might be phosphorylated in the step of degradation of CA protein oligomers. Several active compounds were found and might become new anti-HIV agents and new tools for elucidation of CA functions.