Figure 2. Strategies for targeting tetraspanins.

a | Monoclonal antibodies (mAbs) might interfere with tetraspanins by blocking lateral interactions, although this has not yet been well documented. Also, they may sequester tetraspanins, leading to disruption of tetra spanin-enriched domains (TEMs), down-modulation or triggering of apoptosis. In addition, mAbs can be used to deliver a lethal hit to cells expressing particular tetraspanins. For example, the antibody might trigger apoptosis, complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity, or deliver a conjugated toxin or lethal radioisotope or nanoparticle. b | Recombinant soluble large extracelullar loops (sLELs) most probably insert into TEMs, to disrupt lateral interactions among tetraspanins, or between tetraspanins and their partner molecules. In a special case, hepatitis C virus (HCV) infection, the CD81 sLEL acts in trans by binding to the virus and preventing interaction with cellular CD81. c | RNAi strategies are well documented to demonstrate the functional importance of tetraspanins. d | Other approaches might be useful for tetraspanin targeting. For example, a small molecule could be designed to inhibit the interaction of a C-terminal tail with a PDZ-domain protein. A peptide specifically mimicking a tetraspanin transmembrane domain might be effective in disrupting lateral interactions. Interference with the appropriate protein acyl transferase in the Golgi would prevent tetraspanin palmitoylation, leading to an inability to assemble TEMs and resulting in impaired functions.