The NS2B/NS3 serine proteases of the Zika and Dengue
flaviviruses
are attractive targets for the development of antiviral drugs. We
report the synthesis and evaluation of a new, proline-based compound
class that displays allosteric inhibition of both proteases. The structural
features relevant for protease binding and inhibition were determined
to establish them as new lead compounds for flaviviral inhibitors.
Based on our structure–activity relationship studies, the molecules
were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric
binding site in the proteases was probed using mutagenesis and covalent
modification of the obtained cysteine mutants with maleimides, followed
by computational elucidation of the possible binding modes. In infected
cells, antiviral activity against Dengue virus serotype 2 using prodrugs
of the inhibitors was observed. In summary, a novel inhibitor scaffold
targeting an allosteric site shared between flaviviral NS2B/NS3 proteases
is presented whose efficacy is demonstrated in vitro and in cellulo.
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