Design of proteasome inhibitors with oral efficacy in vivo against <i>Plasmodium falciparum</i> and selectivity over the human proteasome

Abstract

The <i>Plasmodium falciparum</i> proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the <i>P. falciparum</i> 20S proteasome (<i>Pf</i>20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of <i>P. falciparum</i> compared with a human cell line and exhibit high potency against field isolates of <i>P. falciparum</i> and <i>Plasmodium vivax</i> They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against <i>P. falciparum</i> infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to <i>Pf</i>20S than to human constitutive 20S (<i>Hs</i>20Sc). Comparison of the cryo-electron microscopy (EM) structures of <i>Pf</i>20S and <i>Hs</i>20Sc in complex with MPI-5 and <i>Pf</i>20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in <i>P. falciparum</i>, underpinning the design of potent and selective antimalarial proteasome inhibitors.