t22-protein--synthetic and plerixafor

Topics: Amino Acid Sequence; Animals; Anti-HIV Agents; Antimicrobial Cationic Peptides; Benzylamines; Chemokine CCL5; Cyclams; Heterocyclic Compounds; HIV-1; Humans; Ligands; Molecular Sequence Data; Oligopeptides; Peptides; Receptors, Chemokine

The engineering of protein self-assembling at the nanoscale allows the generation of functional and biocompatible materials, which can be produced by easy biological fabrication. The combination of cationic and histidine-rich stretches in fusion proteins promotes oligomerization as stable protein-only regular nanoparticles that are composed by a moderate number of building blocks. Among other applications, these materials are highly appealing as tools in targeted drug delivery once empowered with peptidic ligands of cell surface receptors. In this context, we have dissected here this simple technological platform regarding the controlled disassembling and reassembling of the composing building blocks. By applying high salt and imidazole in combination, nanoparticles are disassembled in a process that is fully reversible upon removal of the disrupting agents. By taking this approach, we accomplish here the in vitro generation of hybrid nanoparticles formed by heterologous building blocks. This fact demonstrates the capability to generate multifunctional and/or multiparatopic or multispecific materials usable in nanomedical applications.

Topics: Amino Acid Sequence; Antimicrobial Cationic Peptides; Benzylamines; Cyclams; Gene Expression; HeLa Cells; Heterocyclic Compounds; Humans; Imidazoles; Nanoparticles; Nanotechnology; Particle Size; Peptides; Protein Engineering; Receptors, CXCR4; Recombinant Proteins; Sodium Chloride

CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) variants evolve from CCR5-restricted (R5) HIV-1 variants. Early after their first appearance in vivo, X4 HIV-1 variants additionally use CCR5. The ability to use CCR5 in addition to CXCR4 is generally lost late in infection. Here we studied whether this evolution of the coreceptor repertoire is also reflected in a changing sensitivity of X4 variants to CXCR4 antagonists such as peptide T22 and the synthetic compound AMD3100. We observed differences in the concentrations of CXCR4 antagonists needed to suppress replication of X4 HIV variants from different patients. In general, late X4 HIV variants were less sensitive to AMD3100 than were early R5X4 HIV variants. The differences between early R5X4 HIV variants and late X4 variants were less pronounced for T22-mediated inhibition. These results suggest an ongoing evolution of X4 virus variants toward more efficient usage of the cellular entry complex.

Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antimicrobial Cationic Peptides; Benzylamines; Cell Line; Cyclams; Evolution, Molecular; Genetic Variation; Heterocyclic Compounds; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Receptors, CXCR4

T22 ([Tyr5,12, Lys7]-polyphemusin II) is an 18-residue peptide amide, which has strong anti-HIV activity. T22 inhibits the T cell line-tropic (T-tropic) HIV-1 infection through its specific binding to a chemokine receptor CXCR4, which serves as a coreceptor for the entry of T-tropic HIV-1 strains. Herein, we report our finding of novel 14-residue CXCR4 inhibitors, T134 and T140, on the basis of the T22 structure. In the assays we examined, T140 showed the highest inhibitory activity against HIV-1 entry and the strongest inhibitory effect on the binding of an anti-CXCR4 monoclonal antibody (12G5) to CXCR4 among all the CXCR4 inhibitors that have been reported up to now.

Topics: Amino Acid Sequence; Anti-HIV Agents; Antimicrobial Cationic Peptides; Benzylamines; Cells, Cultured; Chemokine CXCL12; Chemokines, CXC; Circular Dichroism; Cyclams; DNA-Binding Proteins; Heterocyclic Compounds; HIV-1; Molecular Sequence Data; Oligopeptides; Peptides; Peptides, Cyclic; Receptors, CXCR4; T-Lymphocytes