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A Chemical Inhibitor of Heat Shock Protein 78 (HSP78) From Leishmania Donovani Represents a Potential Anti-Leishmanial Drug Candidate

A Chemical Inhibitor of Heat Shock Protein 78 (HSP78) From Leishmania Donovani Represents a Potential Anti-Leishmanial Drug Candidate

Sonali Das, Anindyajit Banerjee, Mohd Kamran, Sarfaraz Ahmad Ejazi, Mohammad Asad, Nahid Ali, Saikat Chakrabarti

J Biol Chem. 2020 May 29;jbc.RA120.014587.

PMID: 32471865

Abstract:

Emergence of resistance to available anti-leishmanial drugs advocates identification of new drug targets and their inhibitors for visceral leishmaniasis. Here, we identified heat shock protein 78 in Leishmania donovani (LdHSP78), a putative ClpB protease, as important for parasite infection of host macrophages and a potential therapeutic target. Enrichment of LdHSP78 in infected humans, hamsters and parasite amastigotes suggested its importance for disease persistence. Heterozygous knockouts of L. donovani (LdHSP78+/-) and L. mexicana (LmxHSP78+/-) were generated using flanking untranslated region (UTR) based multi-fragment ligation strategy and CRISPR-Cas9 technique, respectively to investigate the significance of HSP78 for disease manifestation. LdHSP78+/- parasite burden was dramatically reduced in both murine bone marrow-derived macrophages and hamsters, associated with enrichment of pro-inflammatory cytokines and nitric oxide (NO). This finding implies that LdHSP78+/- parasites cannot suppress immune activation and escape NO-mediated toxicity in macrophages. Further, phosphorylation of the mitogen-activated protein kinase (MAPK) p38 was enhanced, and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was decreased in cells infected with LdHSP78+/- compared to wildtype (WT) infection. Virulence of the LdHSP78+/- strain was restored by episomal addition of LdHSP78 gene. Finally, using high-throughput virtual screening, we identified P1,P5-di(adenosine-5')-penta-phosphate ammonium salt (Ap5A) as an LdHSP78 inhibitor. It selectively induced amastigote death at doses similar to amphotericin B (AmB) dosing, while exhibiting much less cytotoxicity toward healthy macrophages than AmB. In summary, using both a genetic knockout approach and pharmacological inhibition, we establish LdHSP78 as a drug target and Ap5A as a potential lead for improved anti-leishmanial agents.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415813	P1,P5-Di(adenosine-5′) pentaphosphate ammonium salt			Price

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