Anthracene-based inhibitors of dengue virus NS2B–NS3 protease☆

Abstract

SummaryDengue virus (DENV) is a mosquito-borne flavivirus that has strained global healthcare systems throughout tropical and subtropical regions of the world. In addition to plaguing developing nations, it has re-emerged in several developed countries with recent outbreaks in the USA (CDC, 2010), Australia (Hanna et al., 2009), Taiwan (Kuan et al., 2010 and France (La Ruche et al., 2010). DENV infection can cause significant disease, including dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and death. There are no approved vaccines or antiviral therapies to prevent or treat dengue-related illnesses. However, the viral NS2B-NS3 protease complex provides a strategic target for antiviral drug development since NS3 protease activity is required for virus replication. Recently, we reported two compounds with inhibitory activity against the DENV protease in vitro and antiviral activity against dengue 2 (DEN2V) in cell culture (Tomlinson et al., 2009a). Analogs of one of the lead compounds were purchased, tested in protease inhibition assays, and the data evaluated with detailed kinetic analyses. A structure activity relationship (SAR) identified key atomic determinants (i.e. functional groups) important for inhibitory activity. Four "second series" analogs were selected and tested to validate our SAR and structural models. Here, we report improvements to inhibitory activity ranging between ~2-and 60-fold, resulting in selective low micromolar dengue protease inhibitors.

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

“…and C 29 H 25 N 3 O 4 S, CID 54710332; Figure 1) and Ile165 were also reported by Salaemae et al [63] as determinants of binding with the substrate in the active site of the dengue virus NS3 protease, as was also noted by other authors [35,64,65].…”

“…The bioassay used here is a modification of that reported by Tomlinson and Watowich [35]. The molecules used were those that were commercially available, with the best inhibitor concentration [36].…”

“…An important parameter for the interpretation of the antiviral of a compound tested by using cell-based assays is the SI (SI = CC 50 /IC 50 ). Table 2 and Table S3) include some compounds with specific mode of inhibition for different dengue serotypes like C10 [54]; others, that interact with conserved residues of the catalytic triad and the active site, decreasing the likelihood of drug-resistant mutations, like CID 4101471 and ARDP0006 [35] or Chemdiv K286-0036 [55]; or forming hydrogen bonds with the P4 region, a specificity determinant of dengue virus NS3 protease [59], like CID 60194816 and CID 60194819 [56] or finally compounds 7b, 7c, 7e, 8a, 8b and 8e with inhibitory rates over 75% and IC 50 values lower than 5 µM [57].…”

Computational Design of Dengue Type-2 NS2B/NS3 Protease Inhibitor: 2D/3D QSAR of Quinoline and Its Molecular Docking

“…Up to now, there has been some published compounds exhibiting nano to micro molar inhibition ranges against DENV2 NS2B/NS3pro such as tetrapeptide with electrophilic covalent warhead [12], panduratin derivatives [18], α-ketoamide [19], acrylamide [20], anthracene [21], quinoline [22], aminobenzamide [23], benzothiazole and oxadiazole [24]. Unfortunately, neither peptidomimetic nor small molecule compounds are able to enter the clinical stage as a drug candidate [19].…”

High throughput virtual screening based discovery of dengue protease inhibitor

“…Polyprotein comprising of three structural (C, prM, M) and seven non-structural proteins (NS1,NS2A,NS2B,NS3,NS4A,NS4B and NS5) is further processed by host proteases and NS2B-NS3 viral protease, a major characteristic of the viral life cycle and replication performance. Consequently, the protease inhibition can be a successful way to fight against DENV infection [10][11][12][13][14] . Located in the N-terminal region, NS3 is a multifunctional protein that comprises of 180 amino acids of NS3 protease.…”