Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
The cellular ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3) is an essential host factor for the replication of viruses causing major human diseases, such as HIV-1 or Hepatitis C (HCV), as well as orphan diseases, such as Dengue virus (DENV), West-Nile virus (WNV), Human T-cell leukemia Virus (HTLV)-1 and Japanese Encephalitis Virus (JEV) . Despite being an increasing threat, no specific and effective therapy is currently available for the latter pathogens. The classical antiviral approach targets viral proteins and has an important Achilles’ heel: the emergence of viral resistance to the drugs. Conversely, targeting a cellular factor that is required for viral replication could overcome this problem and be effective against all viruses that are dependent on the same host factor. Following this approach, our research group is working in targeting both the ATPase and RNA binding regions of the host protein DDX3 [2-6]. Most of the synthesized derivatives are able to inhibit DDX3 helicase activity at sub-micromolar concentration, and show a good inhibition in cells of HCV, HIV JEV, DENV and WNV infections. Our results clearly demonstrate that DDX3 inhibitors could be exploited for the treatment of major clinical challenges, such as HIV/HCV co-infections, HIV-1 resistant strains and emerging viruses.
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