Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and <i>Leishmania</i> Hsp90s

Mohammadi-Ostad-Kalayeh, Sona; Stahl, Frank; Scheper, Thomas; Kock, Klaus; Herrmann, Christian; Batista, Fernanda Aparecida Heleno; Borges, Júlio César; Sasse, Florenz; Eichner, Simone; Ongouta, Jekaterina; Zeilinger, Carsten; Kirschning, Andreas

doi:10.1002/cbic.201700616

Cited by 17 publications

(13 citation statements)

References 48 publications

(28 reference statements)

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“…Reinforcing our results, some derivatives of reblastatin, a GA-related compound, were recently shown to exhibit increased binding to L . braziliensis Hsp83 than to human Hsp90 23 . Similarly, Kanwar et al .…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

Palma

Ferreira

Petersen

et al. 2019

Sci Rep

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Leishmaniasis is a neglected disease that affects millions of individuals around the world. Regardless of clinical form, treatment is based primarily on the use of pentavalent antimonials. However, such treatments are prolonged and present intense side effects, which lead to patient abandonment in many cases. The search for chemotherapeutic alternatives has become a priority. Heat Shock Protein 90 (Hsp90) inhibitors have recently come under investigation due to antiparasitic activity in Plasmodium sp., Trypanosoma sp. and Leishmania sp. Some of these inhibitors, such as geldanamycin and its analogs, 17-AAG and 17-DMAG, bind directly to Hsp90, thereby inhibiting its activity. Previous studies have demonstrated that different parasite species are more susceptible to some of these inhibitors than host cells. We hypothesized that this increased susceptibility may be due to differences in binding of Hsp90 inhibitors to Leishmania protein compared to host protein. Based on the results of the in silico approach used in the present study, we propose that geldanamycin, 17-AAG and 17-DMAG present an increased tendency to bind to the N-terminal domain of Leishmania amazonensis Hsp83 in comparison to human Hsp90. This could be partially explained by differences in intermolecular interactions between each of these inhibitors and Hsp83 or Hsp90. The present findings demonstrate potential for the use of these inhibitors in the context of anti-Leishmania therapy.

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Section: Discussionmentioning

confidence: 86%

“…Recently, derivatives of reblastatin, a GA-related compound, have been shown to bind to L . braziliensis Hsp83 and exert inhibitory activity over this protein 23 . Treatment with 17-AAG was further shown to reduce the percentage of macrophages infected by L .…”

Section: Introductionmentioning

confidence: 99%

A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

Palma

Ferreira

Petersen

et al. 2019

Sci Rep

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“…This suggests that co-chaperones of Hsp90 may augment parasite drug resistance, and such a phenomenon would further justify the importance of combinational therapies against parasitic infections. Leishmania braziliensis Hsp90 (LbHsp90) was shown to be selectively targeted by alkynyl substituents of reblastatin (Figure 2) obtained from Streptomyces hygroscopicus (GA producer) [79]. Thus, identification of species-specific Hsp90 inhibitors remains a promising agenda.…”

Section: Hsp90 Familymentioning

confidence: 99%

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

Zininga

Shonhai

2019

IJMS

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Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.

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“…We recently reported that the position of the fluorescence label attached to ATP can influence the binding to Hsps. 25 With respect to sterically congested gambogic acid (1), one may consider uncompetitive effects instead. Therefore, we included a modified orthogonal assay in our studies.…”

Section: ■ Conformation Of Gba-binding By Mstmentioning

confidence: 99%

“…The studies revealed that different Hsps have different susceptibilities to the test compounds. 22,25 Surprisingly, ATP displacement was also induced by gambogic acid (1), which supposedly binds outside the ATP-binding pocket (Figure S3). In addition, orthogonal MST experiments revealed that ATP is required for the binding of 1.…”

Section: ■ Conclusionmentioning

confidence: 99%

The Noncompetitive Effect of Gambogic Acid Displaces Fluorescence-Labeled ATP but Requires ATP for Binding to Hsp90/HtpG

et al. 2018

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The heat shock protein 90 (Hsp90) family plays a critical role in maintaining the homeostasis of the intracellular environment for human and prokaryotic cells. Hsp90 orthologues were identified as important target proteins for cancer and plant disease therapies. It was shown that gambogic acid (GBA) has the potential to inhibit human Hsp90. However, it is unknown whether it is also able to act on the bacterial high-temperature protein (HtpG) analogue. In this work, we screened GBA and nine other novel potential Hsp90 inhibitors using a miniaturized high-throughput protein microarray-based assay and found that GBA shows an inhibitory effect on different Hsp90s after dissimilarity analysis of the protein sequence alignment. The dissociation constant of GBA and HtpG Xanthomonas (XcHtpG) computed from microscale thermophoresis is 682.2 ± 408 μM in the presence of ATP, which is indispensable for the binding of GBA to XcHtpG. Our results demonstrate that GBA is a promising Hsp90/HtpG inhibitor. The work further demonstrates that our assay concept has great potential for finding new potent Hsp/HtpG inhibitors.

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Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Cited by 17 publications

References 48 publications

A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

The Noncompetitive Effect of Gambogic Acid Displaces Fluorescence-Labeled ATP but Requires ATP for Binding to Hsp90/HtpG

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