Virology & Mycology
Open Access

Signal peptide-binding drug as a selective CD4 receptor down-modulator with anti-HIVactivity

International Conference on Retroviruses & Novel Drugs

June 08-09, 2015 Chicago, USA

Kurt Vermeire

Posters-Accepted Abstracts: Virol-mycol

Abstract :

Human Immunodeficiency Virus (HIV) uses the human CD4 protein (hCD4) as the primary surface receptor for attachment and infection of host cells such as CD4+Th-lymphocytes. This hCD4 receptor dependency can be exploited in an antiviral strategy: Removal of the CD4 receptor from the cell surface will prevent HIV infection of target cells and viral replication. In eukaryotic cells, surface expression of most transmembrane proteins is dependent on the presence of a hydrophobic N-terminal signal peptide (SP) on nascent proteins. It facilitate stargeting of the nascent proteins to the Sec61 translocon, a universally conserved protein-conducting channel in the ER-membrane, and subsequent insertion of the chain for translocation. Despite their common function, signal peptides have diverse primary sequences. Thus, drugs that recognize uniquesignal peptide sequences could be exploited to inhibit translocation of selected proteinsin to the ER and their expression at the cell surface. Previously, the small-molecule macrocycle CADA was identified as an antiviral drug with broad spectrum anti-HIV activity. It acts as a highly selective hCD4 expression down-modulator. Here we show that CADA inhibitsh CD4 biogenesis by preventing co-translational translocation of hCD4 to the ER lumen, both in cell culture andin a cell-free in vitro translation/translocation system. The activity of CADA maps to the signal peptide of hCD4 which represents the minimal sequence requested for full CADA sensitivity. Importantly, we could show direct binding between this SP and CADA through suface plasmon resonance (SPR). Further more, translocation inhibition by CADA causes the precursor protein to be routed to the cytosol for degradation. These findings demonstrate that a synthetic, cell-permeable small-molecule such as CADA can act as a signal peptide-binding drug to regulate the expression of specific target proteins by selective and reversible inhibition of protein translocation.