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Related Concept Videos

The Proteasome01:13

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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The Proteasome Structure01:17

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
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Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
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Biological Methods for Microbial Control01:28

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Biological agents offer an effective means of controlling microbial growth by leveraging natural processes like predation, competition, and the secretion of antimicrobial substances.Predatory bacteria such as Bdellovibrio species target and kill pathogens like Salmonella and E. coli. They are widely used in poultry farms to control infections. Myxococcus species help combat plant-pathogenic fungi. These naturally occurring predators serve as eco-friendly alternatives to chemical pesticides and...
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Antimicrobial Proteins01:23

Antimicrobial Proteins

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Antimicrobial proteins are important components of the immune system. They aid the body in combating pathogens by either killing them directly or hindering their replication processes. Four main types of antimicrobial substances are interferons, the complement system, iron-binding proteins, and antimicrobial proteins.
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Microorganisms in Medicine and Therapeutics01:29

Microorganisms in Medicine and Therapeutics

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Microorganisms play a fundamental role in vaccine development, gene therapy, and therapeutic production. Their biological properties are harnessed to advance medicine and public health. Beyond immunization, microorganisms contribute to gut health, antibiotic synthesis, and genetic disease treatment.Live Attenuated and Inactivated VaccinesLive attenuated vaccines, such as the measles, mumps, and rubella (MMR) vaccine, utilize weakened forms of pathogens to closely resemble natural infections.
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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Microbial proteasomes as drug targets.

Hao Zhang1, Gang Lin1

  • 1Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York, United States of America.

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Proteasome inhibitors are revolutionizing cancer treatment and show promise against microbial infections. Research focuses on developing selective inhibitors for microbial proteasomes, targeting diseases like leishmaniasis and Chagas disease.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Proteasomes are essential ATP-dependent hydrolases crucial for intracellular protein turnover, present in all kingdoms of life.
  • Pharmacological proteasome inhibition is detrimental to cell viability, with proteasome inhibitors transforming multiple myeloma treatment.

Purpose of the Study:

  • To review strategies and pharmacophores for developing proteasome inhibitors selective for microbial targets.
  • To highlight clinical proteasome inhibitor candidates for leishmaniasis and Chagas disease.
  • To discuss future challenges and therapeutic potential of microbial proteasome inhibitors.

Main Methods:

  • Review of scientific literature on proteasome inhibitor development.
  • Analysis of strategies and pharmacophores for selective microbial proteasome inhibition.
  • Highlighting clinical development of proteasome inhibitor candidates.

Main Results:

  • Significant progress has been made in developing inhibitors selective for microbial proteasomes, particularly starting with Mycobacterium tuberculosis (Mtb).
  • Proteasomes in pathogenic microbes like Mtb and Plasmodium falciparum (Pf) are validated therapeutic targets.
  • Clinical proteasome inhibitor candidates are emerging for treating leishmaniasis and Chagas disease.

Conclusions:

  • Developing potent and selective proteasome inhibitors that spare human proteasomes is a key strategy.
  • Microbial proteasome inhibitors hold significant therapeutic potential for neglected tropical diseases.
  • Further research is needed to address challenges and fully realize the potential of these inhibitors.