d-Proline-based peptidomimetic inhibitors of anthrax lethal factor

In this work we reported the generation of d-proline-derived hydroxamic acids as inhibitors of anthrax lethal factor (LF), taking advantage of a pyrrolidine ring as the central scaffold and a hydroxamate group as the Zn2+ chelating agent. The introduction of two hydrophobic groups addressing the S1′ subsite and a long substrate-binding groove was conceived by overlapping the bioactive conformations of two reported LF inhibitors. Micromolar affinity of compound 38 suggested cis-3-substituted-1-sulfonamido-d-proline hydroxamic acids as a promising class of peptidomimetic inhibitors for developing novel LF inhibitors.

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► Substrate-based drug design using coordinates of two different LF inhibitors.
► Synthesis of d-proline-derived inhibitors of anthrax lethal factor (LF).
► 3-Substituted-compounds increase enzyme inhibition potency.
► Hit compounds address S1′ subsite and a long substrate-binding groove.