Small Molecule Pan-Dengue and West Nile Virus NS3 Protease Inhibitors

Abstract

Background Dengue fever, dengue hemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV) and are an increasing global health risk. The related West Nile Virus (WNV) causes significant morbidity and mortality as well and continues to be a threat in endemic areas. Currently no FDA approved vaccines or therapeutics are available to prevent or treat any of these infections. Like the other members of the Flaviviridae family, DENV and WNV encode a protease (NS3) which is essential for viral replication and therefore is a promising target for developing therapies to treat dengue and West Nile infections. Methods Flaviviral protease inhibitors were identified and biologically characterized for mechanism of inhibition and DENV anti-viral activity. Results A guanidinylated 2, 5-dideoxystreptamine class of compounds was identified that competitively inhibited the NS3 protease from DENV(1-4) and WNV with IC50 values in the 1-70 μM range. Cytotoxicity was low; however, antiviral activity versus DENV-2 on VERO cells was not detectable. Conclusions This class of compounds is the first to demonstrate competitive pan-dengue and WNV NS3 protease inhibition and, given the sequence conservation among flavivirus NS3 proteins, suggests that developing a pan-dengue or possibly pan-flavivirus therapeutic is feasible.

Inhibition of Dengue virus and West Nile virus proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives

“…Consequently, there has been an increasing interest in the discovery and development of agents for DENV infection. 19 …”

“…19,37-38 Consequently, the synthesized compounds were also screened against WNV NS2B-NS3pro 27 and the results are summarized in Figure 3. Compounds 4l and 7j-n displayed weak inhibitory activity toward the enzyme.…”

“…9-10 X-ray crystal structures of NS2B-NS3pro of WNV and DENV-2 and DENV-1 have been reported. 11-14 Inhibitors of NS2B-NS3 protease containing a highly charged peptidyl recognition element with a dibasic motif at P 1 -P 2 coupled to an array of electrophilic warhead (aldehydes, trifluoromethyl ketones, and boronic acids) 15-17 or non-peptidyl α-ketoamides, 18 and others 19-20 have been described.…”

New Binding Site Conformations of the Dengue Virus NS3 Protease Accessed by Molecular Dynamics Simulation

“…This protease has already been recognized as a valuable target for the design of new antiviral inhibitors against Dengue virus [15,16], and, therefore, designing potent inhibitors against DENV NS3 PRO is an active research line in the fight against DF [17–22]. The use of computational drug-design approaches would be useful here to improve the discovery of putative hits and to help obtain new leads [23–31].…”

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

“…Given the high amino acid sequence homology between the NS3 proteases of the Flaviviridae family [45], it is feasible that the inhibitors reported for other viral proteases might have an important inhibitory activity for this enzyme in dengue virus. For this reason, the crystal structure of the dengue NS2B/NS3 protease (PDB: 2FOM) was docked with some inhibitors that were reported for proteases from viruses, such as Hepatitis C (HCV), West Nile (WNV), Dengue and Human Immunodeficiency Virus (HIV) ( Table 2).…”