LAUSR

Simple Summary Novel therapeutic targets are needed to improve treatments of aggressive cancers and viral diseases. Tetraspanins represent an emerging class of anticancer targets, notably the transmembrane protein CD81 which has been structurally well characterized. CD81 plays key roles in tumor growth and dissemination, and serves as a co-receptor for a number of viruses. The protein interacts with a variety of protein partners involved in different signaling pathways. Here, we provide an overview of the complementary approaches used to target CD81, with monoclonal antibodies and small molecules, including both natural products and synthetic compounds. Drug design approaches are discussed, as well as the limitations associated with the targeting of this ubiquitous protein. CD81 is considered as a promising anticancer and antiviral target. Abstract Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also an anticancer target implicated in cancer cell proliferation and mobility, and in tumor metastasis. CD81 signaling contributes to the development of solid tumors (notably colorectal, liver and gastric cancers) and has been implicated in the aggressivity of B-cell lymphomas. A variety of protein partners can interact with CD81, either to regulate attachment and uptake of viruses (HCV E2, claudin-1, IFIM1) or to contribute to tumor growth and dissemination (CD19, CD44, EWI-2). CD81-protein interactions can be modulated with molecules targeting the extracellular domain of CD81, investigated as antiviral and/or anticancer agents. Several monoclonal antibodies anti-CD81 have been developed, notably mAb 5A6 active against invasion and metastasis of triple-negative breast cancer cells. CD81-EC2 can also be targeted with natural products (trachelogenin and harzianoic acids A-B) and synthetic compounds (such as benzothiazole-quinoline derivatives). They are weak CD81 binders but offer templates for the design of new compounds targeting the open EC2 loop. There is no anti-CD81 compound in clinical development at present, but this structurally well-characterized tetraspanin warrants more substantial considerations as a drug target.