Bortezomib Warhead-Switch Confers Dual Activity against Mycobacterial Caseinolytic Protease and Proteasome and Selectivity against Human Proteasome

Frontiers in Microbiology
Wilfried MoreiraThomas Dick

Abstract

Mycobacteria harbor two main degradative proteolytic machineries, the caseinolytic protease ClpP1P2 and a proteasome. We recently showed that Bortezomib inhibits ClpP1P2 and exhibits whole cell activity against Mycobacterium tuberculosis. Bortezomib, a dipeptide with a boronic acid warhead, is a human proteasome inhibitor approved for cancer therapy. The boronic acid warhead of the compound has been shown to drive potency against both the human proteasome and ClpP1P2 protease. Selectivity for the bacterial ClpP1P2 protease over the human proteasome is lacking but needs to be achieved to move this new anti-tuberculosis lead forward. In this study we explored whether an alternative warhead could influence Bortezomib's selectivity. We synthesized an analog containing a chloromethyl ketone instead of the boronic acid warhead and determined potencies against the bacterial and human enzymes. Surprisingly, the analog retained activity against mycobacterial ClpP1P2 and was active against the mycobacterial proteasome, but was devoid of activity against the human proteasome. Interrogation of a set of chloromethyl ketone peptides identified three additional compounds similarly inhibiting both ClpP1P2 and the proteasome in the bacteria whi...Continue Reading

References

Dec 15, 1993·The Biochemical Journal·P J SavoryA J Rivett
Jan 1, 1999·Bioorganic & Medicinal Chemistry Letters·J AdamsR L Stein
Jun 27, 2002·Current Topics in Microbiology and Immunology·M Bogyo, E W Wang
May 19, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert C KaneRichard Pazdur
Sep 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert C KaneRichard Pazdur
Jun 19, 2008·Annual Review of Microbiology·Kenneth C Keiler
Apr 17, 2012·Molecular Cell·Paula C A da FonsecaEdward P Morris
Oct 15, 2013·International Journal of Medical Microbiology : IJMM·Heike Brötz-Oesterhelt, Peter Sass
Oct 1, 2014·Proceedings of the National Academy of Sciences of the United States of America·Karl R SchmitzRobert T Sauer

❮ Previous
Next ❯

Citations

Mar 4, 2020·Proceedings of the National Academy of Sciences of the United States of America·Siavash VahidiLewis E Kay
Feb 27, 2018·Current Opinion in Microbiology·Joanna C Evans, Valerie Mizrahi
May 7, 2021·The Journal of Membrane Biology·Ameya D BendreJanesh Kumar
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Paolo Saul CoghiYingjun Zhang
Feb 22, 2018·ACS Infectious Diseases·Tania J LupoliBen Gold

❮ Previous
Next ❯

Methods Mentioned

BETA
co-crystallization
Assay

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.