FIG. 5. Scintillation proximity assay for screening of polymerase (RdPp) inhibitors (Q). A poly C template (■) together with an oligo G20 primer ( □) is incubated with RdPp in the presence of GTP (•) and [ H] GTP (O). Incorporation of radioactivity into the primer strand is measured using SPA beads which are attached to the primer through Streptavidine (♦).
NS3 protease is also a target that looks promising. However the optimization of a lead will be considerably more challenging than for the polymerase. The task will be especially hard if no suitable lead can be found by HTS and a pepti-domimetic approach needs to be adopted. In such a case a multi-year effort will be necessary to optimize pharmacokinetics, especially oral bioavailability.
NS3 helicase, while attractive from a biological standpoint, has proven to be a difficult target for HCV drug discovery. If HTS can identify a lead, then the most challenging aspect of such a project would be to find a compound with sufficient selectivity versus host helicases. This problem should be surmountable with a concerted effort in lead optimization.
Two other potential targets in the flavivirus genome, the SAM domain and E protein, have not been discussed in this short overview. While for both targets structural information is available, we currently do not have enough information to judge whether they are attractive drug targets.
Overall, drug discovery for flaviviral diseases has made great strides in the last two years and there is cause for optimism. It is, however, important to remember that timelines for both preclinical and clinical developments are long and that therefore, even under best conditions, a drug for dengue will not be available to the patients before the start of the next decade.
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