Bioprospecting for Novel Heat Shock Protein Modulators: The New Frontier for Antimalarial Drug Discovery?

Anokwuru, Chinedu P.; Makumire, Stanley; Shonhai, Addmore

doi:10.1007/978-3-030-78397-6_8

Cited by 2 publications

(5 citation statements)

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“…Also, a marine prenylated alkaloid, malonganenone A was shown to possess the antimalarial activity and selectively inhibit plasmodial Hsp70 (Cockburn et al, 2014). Furthermore, terpenoids, which are the most abundant and structurally diverse secondary metabolites, possess a wide range of pharmacological activities, including antimalarial effects and heat shock protein inhibitory activities (Wang et al, 2005;Gabriel et al, 2018;Anokwuru et al, 2021). For instance, gedunin, kotschyins D, celastrol, and fusicoccane have been shown to inhibit Plasmodial Hsp90 and/or induced degradation of Hsp90-dependent client proteins (Westerheide et al, 2004;Brandt et al, 2008;Zhang et al, 2008;Piaz et al, 2012;Patwardhan et al, 2013;D'Ambola et al, 2019).…”

Section: Structural Formula Referencesmentioning

confidence: 99%

“…Today, small molecule inhibition of plasmodial heat shock proteins has shown promise in reversing P. falciparum - induced drug resistance, while also synergizing with traditional antimalarial drugs ( Shahinas et al, 2013b ; Cockburn et al, 2014 ; Posfai et al, 2018 ). Chalcones, polyphenols, terpenoids, alkaloids, and peptides are among the well-tested classes of small molecule inhibitors of heat shock proteins Table 1 [reviewed here ( Anokwuru et al, 2021 ; Daniyan, 2021 )]. While there are evidence that some may help in preventing the breakdown of the blood-brain barrier (BBB) ( Kam et al, 2012 ), their potential usefulness in cerebral malaria is largely unexplored.…”

Section: Potential Usefulness Of Known Chaperones Targeted Small Mole...mentioning

confidence: 99%

“…It is tempting to postulate that celastrol may find usefulness in cerebral malarial as evidence has shown that increased expression of Hsp70 prevents the production of inflammatory mediators via inhibition of NF_ kB , ( Kempaiah et al, 2016 ). In addition, a peptide antibiotic, polymyxin B, and an immunosuppressant, deoxyspergualin, have also demonstrated antimalarial activities ( Anokwuru et al, 2021 ). Polymyxin B showed inhibitory activities on PfHsp70-1 (PF3D7_0818900) and PfHsp70-z (PF3D7_0708800) ( Zininga et al, 2017a ).…”

Section: Potential Usefulness Of Known Chaperones Targeted Small Mole...mentioning

confidence: 99%

“…They are not just serving as sources of drug candidates, they have and still are been used in traditional medicine as worthy alternatives to orthodox drugs ( Ahmad et al, 2006 ; Amoateng et al, 2018 ). Many of the tested small molecules are from these natural sources [reviewed here ( Anokwuru et al, 2021 ; Daniyan, 2021 )]. Many medicinal plant products have shown antimalarial, and/or neuroprotective abilities ( Kaur et al, 2009 ; Mahomoodally, 2013 ; Amoateng et al, 2018 ; Erhirhie et al, 2021 ), and may therefore find usefulness in the management of cerebral malarial.…”

Section: Searching For New Drug Candidates From Natural Productsmentioning

confidence: 99%

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Neurotransmitters and molecular chaperones interactions in cerebral malaria: Is there a missing link?

Daniyan

Fisusi

Adeoye

2022

Front. Mol. Biosci.

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Plasmodium falciparum is responsible for the most severe and deadliest human malaria infection. The most serious complication of this infection is cerebral malaria. Among the proposed hypotheses that seek to explain the manifestation of the neurological syndrome in cerebral malaria is the vascular occlusion/sequestration/mechanic hypothesis, the cytokine storm or inflammatory theory, or a combination of both. Unfortunately, despite the increasing volume of scientific information on cerebral malaria, our understanding of its pathophysiologic mechanism(s) is still very limited. In a bid to maintain its survival and development, P. falciparum exports a large number of proteins into the cytosol of the infected host red blood cell. Prominent among these are the P. falciparum erythrocytes membrane protein 1 (PfEMP1), P. falciparum histidine-rich protein II (PfHRP2), and P. falciparum heat shock proteins 70-x (PfHsp70-x). Functional activities and interaction of these proteins with one another and with recruited host resident proteins are critical factors in the pathology of malaria in general and cerebral malaria in particular. Furthermore, several neurological impairments, including cognitive, behavioral, and motor dysfunctions, are known to be associated with cerebral malaria. Also, the available evidence has implicated glutamate and glutamatergic pathways, coupled with a resultant alteration in serotonin, dopamine, norepinephrine, and histamine production. While seeking to improve our understanding of the pathophysiology of cerebral malaria, this article seeks to explore the possible links between host/parasite chaperones, and neurotransmitters, in relation to other molecular players in the pathology of cerebral malaria, to explore such links in antimalarial drug discovery.

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Section: Structural Formula Referencesmentioning

confidence: 99%

Section: Potential Usefulness Of Known Chaperones Targeted Small Mole...mentioning

confidence: 99%

Section: Potential Usefulness Of Known Chaperones Targeted Small Mole...mentioning

confidence: 99%

Section: Searching For New Drug Candidates From Natural Productsmentioning

confidence: 99%

See 2 more Smart Citations

Neurotransmitters and molecular chaperones interactions in cerebral malaria: Is there a missing link?

Daniyan

Fisusi

Adeoye

2022

Front. Mol. Biosci.

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“…Survival of the malaria parasite inside the host and the vector depends on the action of molecular chaperones. The emergence of resistance to the most commonly used antimalarial drugs, coupled with the difficulty in producing an effective vaccine, resulted in an urgent need to develop drugs targeted against novel chemotherapeutic targets [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Hsp90 and Associated Co-Chaperones of the Malaria Parasite

et al. 2022

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Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been extensively studied in many prokaryotic and higher eukaryotic model organisms, its structural, functional, and biological properties in parasitic protozoans are less well defined. Hsp90 collaborates with a wide range of co-chaperones that fine-tune its protein folding pathway. Co-chaperones play many roles in the regulation of Hsp90, including selective targeting of client proteins, and the modulation of its ATPase activity, conformational changes, and post-translational modifications. Plasmodium falciparum is responsible for the most lethal form of human malaria. The survival of the malaria parasite inside the host and the vector depends on the action of molecular chaperones. The major cytosolic P. falciparum Hsp90 (PfHsp90) is known to play an essential role in the development of the parasite, particularly during the intra-erythrocytic stage in the human host. Although PfHsp90 shares significant sequence and structural similarity with human Hsp90, it has several major structural and functional differences. Furthermore, its co-chaperone network appears to be substantially different to that of the human host, with the potential absence of a key homolog. Indeed, PfHsp90 and its interface with co-chaperones represent potential drug targets for antimalarial drug discovery. In this review, we critically summarize the current understanding of the properties of Hsp90, and the associated co-chaperones of the malaria parasite.

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Bioprospecting for Novel Heat Shock Protein Modulators: The New Frontier for Antimalarial Drug Discovery?

Cited by 2 publications

References 86 publications

Neurotransmitters and molecular chaperones interactions in cerebral malaria: Is there a missing link?

Neurotransmitters and molecular chaperones interactions in cerebral malaria: Is there a missing link?

Hsp90 and Associated Co-Chaperones of the Malaria Parasite

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