7LXT

Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.

(2021) Proc Natl Acad Sci U S A 118

• PubMed: 34548400 Search on PubMedSearch on PubMed Central
• DOI: 10.1073/pnas.2107213118
• Primary Citation of Related Structures:  
  7LXT, 7LXU, 7LXV


• PubMed Abstract: 
  

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome ( Pf 20S) β5 active site and that exhibit fast-acting antimalarial activity ...

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome ( Pf 20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax 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 P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf 20S than to human constitutive 20S ( Hs 20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf 20S and Hs 20Sc in complex with MPI-5 and Pf 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 P. falciparum , underpinning the design of potent and selective antimalarial proteasome inhibitors.

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Organizational Affiliation: 

Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia; ltilley@unimelb.edu.au sandy.gould@takeda.com.


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