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HIV-1 capsid assembly inhibitor (CAI) peptide: structural preferences and delivery into human embryonic lung cells and lymphocytes.

ABSTRACT: The Human immunodeficiency virus 1 derived capsid assembly inhibitor peptide (HIV-1 CAI-peptide) is a promising lead candidate for anti-HIV drug development. Its drawback, however, is that it cannot permeate cells directly. Here we report the transport of the pharmacologically active CAI-peptide into human lymphocytes and Human Embryonic Lung cells (HEL) using the BioShuttle platform. Generally, the transfer of pharmacologically active substances across membranes, demonstrated by confocal laser scanning microscopy (CLSM), could lead to a loss of function by changing the molecule's structure. Molecular dynamics (MD) simulations and circular dichroism (CD) studies suggest that the CAI-peptide has an intrinsic capacity to form a helical structure, which seems to be critical for the pharmacological effect as revealed by intensive docking calculations and comparison with control peptides. This coupling of the CAI-peptide to a BioShuttle-molecule additionally improved its solubility. Under the conditions described, the HIV-1 CAI peptide was transported into living cells and could be localized in the vicinity of the mitochondria.

SUBMITTER: Braun K

PROVIDER: S-EPMC2500149 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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HIV-1 capsid assembly inhibitor (CAI) peptide: structural preferences and delivery into human embryonic lung cells and lymphocytes.

Braun Klaus K Frank Martin M Pipkorn Rüdiger R Reed Jennifer J Spring Herbert H Debus Jürgen J Didinger Bernd B von der Lieth Claus-Wilhelm CW Wiessler Manfred M Waldeck Waldemar W

International journal of medical sciences 20080731 5

The Human immunodeficiency virus 1 derived capsid assembly inhibitor peptide (HIV-1 CAI-peptide) is a promising lead candidate for anti-HIV drug development. Its drawback, however, is that it cannot permeate cells directly. Here we report the transport of the pharmacologically active CAI-peptide into human lymphocytes and Human Embryonic Lung cells (HEL) using the BioShuttle platform. Generally, the transfer of pharmacologically active substances across membranes, demonstrated by confocal laser ...[more]

PMID: 18695744

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Project description:The HIV p24 capsid protein has an essential, structural, and functional role in the viral replication cycle, being an interesting target for vaccine design, diagnostic tests, and new antiretroviral drugs (ARVs). The HIV-1 variability poses a challenge for the accuracy and efficiency of diagnostic and treatment tools. This study analyzes p24 diversity among HIV-1 variants and within its secondary structure in HIV-1 M, O, P, and N groups. All available HIV-1 p24 nucleotide sequences were downloaded from the Los Alamos HIV Sequence Database, selecting 23,671 sequences belonging to groups O, N, P, and M (9 subtypes, 7 sub-sub types, and 109 circulating recombinant forms or CRFs). Using a bioinformatics tool developed in our laboratory (EpiMolBio program), we analyzed the amino acid conservation compared to the HXB2 subtype B reference sequence and the V-markers, or amino acid changes that were specific for each variant with at least 10 available sequences. We inferred the p24 consensus sequence for HIV-1 and for each group to analyze the overall conservation in p24 main structural regions, reporting the percentage of substitutions per variant affecting the capsid assembly and molecule-binding, including those associated with resistance to the new capsid-inhibitor lenacapavir, and the key residues involved in lenacapavir-p24 interaction, according to the bibliography. Although the overall structure of p24 was highly conserved, the conservation in the secondary structure varied between HIV-1 variants and the type of secondary structure. All HIV-1 variants presented >80% amino acid conservation vs. HXB2 reference sequence, except for group M sub-subtype F1 (69.27%). Mutants affecting the capsid assembly or lenacapavir capsid-binding were found in <1% of the p24 consensus sequence. Our study reports the HIV-1 variants carrying 14 unique single V-markers in 9/38 group M variants and the level of p24 conservation in each secondary structure region among the 4 HIV-1 groups and group M variants, revealing no natural resistance to lenacapavir in any HIV-1 variant. We present a thorough analysis of p24 variability among all HIV-1 variants circulating to date. Since p24 genetic variability can impact the viral replication cycle and the efficacy of new p24-based diagnostic, therapeutic, and vaccine strategies, conservation studies must consider all HIV-1 variants circulating worldwide.

Dataset Information

HIV-1 capsid assembly inhibitor (CAI) peptide: structural preferences and delivery into human embryonic lung cells and lymphocytes.

Publications

HIV-1 capsid assembly inhibitor (CAI) peptide: structural preferences and delivery into human embryonic lung cells and lymphocytes.

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