A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents

Mundra, Sourabh; Thakur, Vandana; Bello, Angélica M.; Rathore, Sumit; Asad, Mohd; Wei, Lianhu; Yang, Jane; Chakka, Sai Kumar; Mahesh, Radhakrishnan; Malhotra, Pawan; Mohmmed, Asif; Kotra, Lakshmi P.

doi:10.1016/j.bmc.2017.08.049

Cited by 23 publications

(20 citation statements)

References 30 publications

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“…ClpP proteases have emerged as important targets for the development of new classes of antibiotics against bacterial infections (13-15, 17, 18, 68) and for the design of antimalarial agents (20). In humans, ClpP plays a role in the mitochondrial unfolded protein response (69), and its inhibition provides a potential avenue for treating acute myeloid leukemia (22) protected against obesity when administered a fat-rich diet (70).…”

Section: Discussionmentioning

confidence: 99%

“…This novel mode of action was shown to kill Mycobacterium tuberculosis (17) and antibioticresistant subpopulations of Staphylococcus aureus that are implicated in chronic and relapsing infections (18). Similarly, an increasing number of compounds including β-lactones and phenyl esters have been shown to inhibit ClpP function in bacteria (19), and some of these have been proposed for the treatment of malaria by targeting ClpP from the malaria parasite (20). Much less is known about the function of ClpP in mitochondria.…”

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confidence: 99%

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Reversible inhibition of the ClpP protease via an N-terminal conformational switch

Vahidi

Ripstein

Bonomi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Protein homeostasis is critically important for cell viability. Key to this process is the refolding of misfolded or aggregated proteins by molecular chaperones or, alternatively, their degradation by proteases. In most prokaryotes and in chloroplasts and mitochondria, protein degradation is performed by the caseinolytic protease ClpP, a tetradecamer barrel-like proteolytic complex. Dysregulating ClpP function has shown promise in fighting antibiotic resistance and as a potential therapy for acute myeloid leukemia. Here we use methyl-transverse relaxation-optimized spectroscopy (TROSY)-based NMR, cryo-EM, biochemical assays, and molecular dynamics simulations to characterize the structural dynamics of ClpP from (SaClpP) in wild-type and mutant forms in an effort to discover conformational hotspots that regulate its function. Wild-type SaClpP was found exclusively in the active extended form, with the N-terminal domains of its component protomers in predominantly β-hairpin conformations that are less well-defined than other regions of the protein. A hydrophobic site was identified that, upon mutation, leads to unfolding of the N-terminal domains, loss of SaClpP activity, and formation of a previously unobserved split-ring conformation with a pair of 20-Å-wide pores in the side of the complex. The extended form of the structure and partial activity can be restored via binding of ADEP small-molecule activators. The observed structural plasticity of the N-terminal gates is shown to be a conserved feature through studies of and ClpP, suggesting a potential avenue for the development of molecules to allosterically modulate the function of ClpP.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reversible inhibition of the ClpP protease via an N-terminal conformational switch

Vahidi

Ripstein

Bonomi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…GNF6702, the selective inhibitor of the kinetoplastid proteasome, is currently undergoing preclinical toxicity studies and could provide additional support for proteasome inhibition as a viable strategy to treat parasitic diseases (70). Expanding the focus to proteasome-like complexes containing ClpP, ClpQ or ClpR proteases is another promising area (3,74,75). The disruption of mitochondrial ClpQY protease complex leads to loss of mitochondrial membrane potential, mitochondrial dysfunction and apoptosis-like cell death in Plasmodium (3,74).…”

Section: Proteasome Inhibitors As Drug Candidatesmentioning

confidence: 99%

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

Krishnan

Williamson

2018

Translational Research

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The proteasome plays a vital role throughout the life cycle as Plasmodium parasites quickly adapt to a new host and undergo a series of morphologic changes during asexual replication and sexual differentiation. Plasmodium carries 3 different types of protease complexes: typical eukaryotic proteasome (26S) that resides in the cytoplasm and the nucleus, a prokaryotic proteasome homolog ClpQ that resides in the mitochondria, and a caseinolytic protease complex ClpP that resides in the apicoplast. In silico prediction in conjunction with immunoprecipitation analysis of ubiquitin conjugates have suggested that over half of the Plasmodium falciparum proteome during asexual reproduction are potential targets for ubiquitination. The marked potency of multiple classes of proteasome inhibitors against all stages of the life cycle, synergy with the current frontline antimalarial, artemisinin, and recent advances identifying differences between Plasmodium and human proteasomes strongly support further drug development efforts.

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“…To investigate the selectivity of the compounds between the P. falciparum parasite and human cells, HeLa cells were employed to assess the general toxicity of the compounds using a resazurin assay as described in previous studies in literature. [35,36] The compounds were tested at a fixed concentration of 20 μM and the results are illustrated in Figure S1 in the Supporting Information plotted in parallel with the viability of 3D7 P. falciparum parasitaemia. At least 70 % HeLa cell viability was observed for the majority of compounds at the tested concentration of 20 μM, implying preferential selectivity for the malaria parasite over mammalian cells.…”

Section: Biological Evaluationmentioning

confidence: 99%

The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction

et al. 2020

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The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α‐aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and ‐resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple‐negative breast cancer cell line. Indication of cross‐resistance was absent for the compounds evaluated against the multi‐resistant Dd2 strain. Structure‐activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α‐carbon and NH group of the α‐amino‐o‐cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor‐groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.

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A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents

Cited by 23 publications

References 30 publications

Reversible inhibition of the ClpP protease via an N-terminal conformational switch

Reversible inhibition of the ClpP protease via an N-terminal conformational switch

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

The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction

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