Host targeted inhibitors of dengue virus and other viruses
a technology of dengue virus and inhibitors, applied in the field of host targeted inhibitors of dengue virus and other viruses, can solve the problems of no specific therapeutics, and achieve the effect of broader inhibitory activity and higher resistance barriers
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example 1
of the Compounds
[0441]The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Various intermediates useful for preparation of the compounds of the invention can be prepared in accordance with methods described in the art (Upasani et al., J. Med. Chem. (1997) 40:73-84; and Hogenkamp et al., J. Med. Chem. (1997) 40:61-72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. Representative methods are demonstrated in Schemes 1-4. The compounds of the invention can be prepared using the intermediates described above. For example, a general method for preparing QL-XII-47 is illustrated in Scheme 1.
[0442]Compounds 1 (480 mg, 2 mmol, 1 equiv.) and 2 (470 mg, 2 mmol, 1 equiv.) were combined in 1,4-dioxane (13 mL) and heated at 100° C. for 4 h, cooled to room temperature, poured into brine, and extracted with ethyl acetate (3×). The organic phase ...
example 2
stal Structure of QL-X-138
[0458]QL-X-138 (see FIG. 7 for the chemical structure), a structural analog of QL-XII-47, has been successfully crystallized with EGFR kinase that contains a cysteine in the same position as the Tec-family kinases (FIG. 7). The structure shows the expected hydrogen bond between the quinoline nitrogen and the “hinge” region amino acid Met793. The pyrazole group is directed towards a hydrophobic pocket at the back of the ATP-pocket which the para-methyl aniline group is nestled beneath the P loop and a covalent bond with Cys797 is apparent.
example 3
d Mini-Screen of Acrylamide-Containing Compounds for the Identification of Novel Covalent Inhibitors of DENV
Methods
[0459]Small molecule screens (Chu et al., Proc. Nat. Acad. Sci. USA (2007) 104:3520-3525) and RNAi (Sessions et al., Nature (2009) 458:1047-1050) have been utilized to identify host factors that are required for Dengue virus (DENV) replication, with a particular interest in host kinases that modulate DENV replication. As an extension of this work, a cell-based mini-screen of a 30-compound subset of acrylamide-containing compounds was performed to identify novel covalent inhibitors of DENV. The compounds were designed to react covalently upon binding in the proper orientation near a reactive cysteine.
[0460]Huh7 cells were seeded in 24-well plates and infected at an MOI (multiplicity of infection) of 1 with 100 μl of DENV2 New Guinea C (DENV2-NGC). Plates were incubated for 1 hour at 37° C. and rocked every 15 min. Unadsorbed virus was removed by a PBS wash, after which 5...
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