Cell-Penetrating Antibodies For Targeting HIV-1 P24 Capsid Protein
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Date
2015-08
Authors
Teow, Sin Yeang
Journal Title
Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
The capsid protein plays seminal roles in both early and late stages of the HIV replication cycle. Hence, HIV-1 capsid protein is considered an important target for developing novel drugs to treat HIV/AIDS. Capsid molecule (CA)-targeting peptide inhibitors (CAP-1, CAI and NYAD-1) have been reported to disrupt the capsid protein functions in HIV-infected cells. However, the peptides are less stable in the blood, thus resulting in rapid clearance from the system and they can exhibit off-target activities. Monoclonal antibodies (MAbs) on the other hand, are stable and highly specific molecule, which have been successfully used as therapeutic modalities to treat various types of cancer and viral infections. Nonetheless, MAbs cannot penetrate into the cell and interact with intracellular target such as HIV-1 CA. To this end, anti-p24 MAbs were chemically engineered with cell-penetrating peptides (CPPs) to generate cell-penetrable (anti-p24-TransMAbs). In this study, anti-p24 MAbs were conjugated with 8 different CPPs through periodate oxidation. The cell penetration of anti-p24-TransMAbs was then examined by p24 ELISA and fluorescence microscopy. Anti-p24 MAbs conjugated with MTS (membrane-transduction sequence) resulted in most efficient penetration into the cells. The internalization of anti-p24-TransMAbs was concentration-dependent and maximum at 24 hours incubation. No toxicity was observed when the cells were treated with up to 10μg/mL anti-p24-TransMAbs. Mechanistic studies showed that the transportation of anti-p24-TransMAbs in promonocytic cell lines was temperature- and energy-dependent, and partially mediated by clathrin and caveolae-dependent endocytic pathways.
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Keywords
Cell-penetrating antibodies for , targeting HIV-1 P24 capsid protein