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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Heat shock protein 90 inhibitors as broad spectrum anti-infectives
Ankit K Rochani1, Meetali Singh, Utpal Tatu
1Department of Biochemistry, Indian Institute of Science, Bangalore-12, India.
Abstract:
Combating stress is one of the prime requirements for any organism. For parasitic microbes, stress levels are highest during the growth inside the host. Their survival depends on their ability to acclimatize and adapt to new environmental conditions. Robust cellular machinery for stress response is, therefore, both critical and essential especially for pathogenic microorganisms. Microbes have cleverly exploited stress proteins as virulence factors for pathogenesis in their hosts. Owing to its ability to sense and respond to the stress conditions, Heat shock protein 90 (Hsp90) is one of the key stress proteins utilized by parasitic microbes. There are growing evidences for the critical role played by Hsp90 in the growth of pathogenic organisms like Candida, Giardia, Plasmodium, Trypanosoma, and others. This review, therefore, explores potential of exploiting Hsp90 as a target for the treatment of infectious diseases. This molecular chaperone has already gained attention as an effective anti-cancer drug target. As a result, a lot of research has been done at laboratory, preclinical and clinical levels for several Hsp90 inhibitors as potential anti-cancer drugs. In addition, lot of data pertaining to toxicity studies, pharmacokinetics and pharmacodynamics studies, dosage regime, drug related toxicities, dose limiting toxicities as well as adverse drug reactions are available for Hsp90 inhibitors. Therefore, repurposing/ repositioning strategies are also being explored for these compounds which have gone through advanced stage clinical trials. This review presents a comprehensive summary of current status of development of Hsp90 as a drug target and its inhibitors as candidate anti-infectives. A particular emphasis is laid on the possibility of repositioning strategies coupled with pharmaceutical solutions required for fulfilling needs for ever growing pharmaceutical infectious disease market.
Insights
Parasitic microbes rely on Heat Shock Protein 90 (Hsp90) for survival and virulence. Targeting Hsp90 offers a promising strategy for developing new anti-infective drugs, potentially by repurposing existing cancer therapies.
Area of Science:
- Microbiology and Molecular Biology
- Drug Discovery and Development
- Parasitology
Background:
- Pathogenic microbes face significant stress within host environments, necessitating robust stress response mechanisms for survival.
- Heat Shock Protein 90 (Hsp90), a key stress protein, plays a critical role in the growth and pathogenesis of various parasitic organisms.
- Hsp90 is recognized for its essential functions in microbial stress response and virulence, making it a potential therapeutic target.
Purpose of the Study:
- To review the current status of Hsp90 as a drug target for infectious diseases.
- To explore the potential of Hsp90 inhibitors as anti-infective agents.
- To investigate the feasibility of repurposing existing Hsp90 inhibitors, developed for cancer treatment, for combating parasitic infections.
Main Methods:
- Literature review of existing research on Hsp90 function in pathogenic microbes.
- Analysis of data on Hsp90 inhibitors, including their development status, toxicity, pharmacokinetics, and pharmacodynamics.
- Exploration of drug repurposing strategies for Hsp90 inhibitors in the context of infectious diseases.
Main Results:
- Hsp90 is crucial for the survival and virulence of diverse pathogenic microbes, including Candida, Giardia, Plasmodium, and Trypanosoma.
- Significant research exists on Hsp90 inhibitors, primarily for anti-cancer applications, with extensive preclinical and clinical data available.
- Existing Hsp90 inhibitors have well-characterized safety profiles and pharmacokinetic properties, suggesting potential for repurposing.
Conclusions:
- Hsp90 represents a viable and attractive drug target for developing novel anti-infective therapies.
- Repurposing established Hsp90 inhibitors offers a strategic advantage due to existing safety and efficacy data, potentially accelerating drug development.
- Further research and pharmaceutical solutions are needed to fully realize the potential of Hsp90 inhibitors in the infectious disease market.
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