An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the Plasmodium falciparum 20S Proteasome

The syringolin natural products are covalent inhibitors
of the
20S proteasome that inspire therapeutic development. Here, we report
a new route to the syringolins amenable to solution and solid-phase
synthesis that overcomes a problematic macrocyclization. Exploiting
our synthetic approach and substrate mimicry models for proteasome
inhibition by the syringolins, we generated a collection of hypothetically
selective inhibitors of the Plasmodium falciparum proteasome, which is an emerging target for antimalarial
drugs. We identified compounds from the library having high second-order
rate constants for Plasmodium proteasome inhibition
and nanomolar antiparasitic activity. They exhibited selectivity for
the Plasmodium proteasome over the human proteasome.
We solved cryo-EM structures of an inhibitor bound to both 20S proteasomes,
revealing key contacts favoring species-selective inhibition. Together,
this work provides an improved route to syringolin analogs, sheds
new light on substrate mimicry by the syringolins, and provides a
structural basis for the pursuit of new antimalarial drugs.