Broad-Spectrum Antimalarial Activity of Peptido Sulfonyl Fluorides, a New Class of Proteasome Inhibitors

Abstract

f Despite declining numbers of cases and deaths, malaria remains a major public health problem in many parts of the world. Today, case management relies heavily on a single class of antimalarial compounds: artemisinins. Hence, development of resistance against artemisinins may destroy current malaria control strategies. Beyond malaria control are elimination and eradication programs that will require drugs with good activity against acute infection but also with preventive and transmission-blocking properties. Consequently, new antimalarials are needed not only to ensure malaria control but also for elimination and eradication efforts. In this study, we introduce peptido sulfonyl fluorides (PSF) as a new class of compounds with antiplasmodial activity. We show that PSF target the plasmodial proteasome and act on all asexual stages of the intraerythrocytic cycle and on gametocytes. PSF showed activities at concentrations as low as 20 nM against multidrug-resistant and chloroquine-sensitive Plasmodium falciparum laboratory strains and clinical isolates from Gabon. Structural requirements for activity were identified, and cytotoxicity in human HeLa or HEK 293 cells was low. The lead PSF PW28 suppressed growth of Plasmodium berghei in vivo but showed signs of toxicity in mice. Considering their modular structure and broad spectrum of activity against different stages of the plasmodial life cycle, proteasome inhibitors based on PSF have a great potential for further development as preclinical candidate compounds with improved species-specific activity and less toxicity.

Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

“…Importantly, our work suggests that a proteasome inhibitor could be used to synergize the activity of ARTs in vivo, and potentially to overcome resistance. Carfilzomib and Bortezomib are FDA-approved for the treatment of multiple myeloma [ 57 ] and inhibitors that specifically target the plasmodial proteasome have been identified [ 39 , 58 , 59 ]. These compounds show low toxicity in human cell lines [ 59 ] and limited toxicity in mice [ 40 , 58 ].…”

“…Carfilzomib and Bortezomib are FDA-approved for the treatment of multiple myeloma [ 57 ] and inhibitors that specifically target the plasmodial proteasome have been identified [ 39 , 58 , 59 ]. These compounds show low toxicity in human cell lines [ 59 ] and limited toxicity in mice [ 40 , 58 ]. In agreement with previous reports, we find that Carfilzomib shows only weak antimalarial activity, when used alone, against the ring-stage of a mouse model of malaria [ 40 ].…”

The proteasome as a target to combat malaria: hits and misses

“…Sulfonyl fluorides were first synthesized and evaluated in 1995 as potent irreversible inhibitors of cysteine proteinases and calpain, and their activity against the proteasome was reported in 1997 (42–44). Tschan et al showed that PSF targets the plasmodium proteasome by binding and inactivating the β-1 and β-5 subunits (45). They further showed that the lead PSF compound PW28 blocks development of asexual stages irrespective of the time of treatment initiation, and that gametocyte development was arrested at all stages, without affecting commitment.…”

Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones

“…21,22 In particular, a N-Cbz protected tetrapeptide incorporating a sulfonyl fluoride unit has demonstrated broad-spectrum antimalarial activity. 23 In this project, we wished to investigate whether a sulfonyl fluoride unit could be incorporated into 5-(4′-nitrophenyl)pyrazole α-amino acid 18. The product of this process would generate a multi-functional compound that would have potential as both a protease inhibitor and could undergo further transformations such as peptide synthesis for development as a biological probe.…”