Macrocyclic Peptides that Selectively Inhibit the <i>Mycobacterium tuberculosis</i> Proteasome

Zhang, Hao; Hsu, Hao-Chi; Kahne, Shoshanna C.; Hara, Ryujiro; Wen-hu, Zhan; Jiang, Xiuju; Burns-Huang, Kristin; Ouellette, Tierra; Imaeda, Toshihiro; Okamoto, Rei; Kawasaki, Masanori; Michino, Mayako; Wong, Tzu‐Tshin; Toita, Akinori; Yukawa, Takafumi; Moraca, Francesca; Vendôme, Jérémie; Saha, Priya; Sato, Kenjiro; Aso, Kazuyoshi; Ginn, John D.; Meinke, Peter T.; Foley, Michael A.; Nathan, Carl; Darwin, K. Heran; Li, Huilin; Lin, Gang

doi:10.1021/acs.jmedchem.1c00296

Cited by 10 publications

(12 citation statements)

References 48 publications

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“…Centrally important to this pathway is the interaction of the AAA unfoldase Mpa with the 20S CP and the recruitment of protein substrates marked by pupylation for degradation by this molecular machine. Despite the significance of this complex as a drug target 44 , structural information on the fully assembled, active protease has been lacking. Our high-resolution cryo-EM structure of the substrate-engaged Mpa–proteasome complex reveals the dynamic character of the interaction between the AAA unfoldase ring and the proteasome core cylinder.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex

et al. 2022

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Proteasomes are present in eukaryotes, archaea and Actinobacteria, including the human pathogen Mycobacterium tuberculosis, where proteasomal degradation supports persistence inside the host. In mycobacteria and other members of Actinobacteria, prokaryotic ubiquitin-like protein (Pup) serves as a degradation tag post-translationally conjugated to target proteins for their recruitment to the mycobacterial proteasome ATPase (Mpa). Here, we use single-particle cryo-electron microscopy to determine the structure of Mpa in complex with the 20S core particle at an early stage of pupylated substrate recruitment, shedding light on the mechanism of substrate translocation. Two conformational states of Mpa show how substrate is translocated stepwise towards the degradation chamber of the proteasome core particle. We also demonstrate, in vitro and in vivo, the importance of a structural feature in Mpa that allows formation of alternating charge-complementary interactions with the proteasome resulting in radial, rail-guided movements during the ATPase conformational cycle.

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Section: Discussionmentioning

confidence: 99%

Structural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex

et al. 2022

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“…Proteasome inhibitor drugs revolutionized the treatment of multiple myeloma, which once was untreatable before the approval of bortezomib in 2003 . Since then, this barrel-shaped, ATP-dependent, compartmentalized, and highly regulated N-terminal threonine hydrolase has emerged as viable targets for drug development against tuberculosis, − malaria, leishmaniasis, and Chagas’ disease. − The very active field of studies offers hope that selective pathogens’ proteasome inhibitors will one day be targeted clinically for the treatment of infectious diseases. Its potential as antimalarial drug target is particularly attractive as the pharmacological inhibition of its function is detrimental to the viability of the parasites at multiple stages of its life cycle, and its synergy with artemisinin, which is the core component of the artemisinin combination therapy of malaria.…”

Section: Discussionmentioning

confidence: 99%

“…The plasma stability of the compounds was determined as previously reported . The human plasma was ordered from Sigma-Aldrich (H3667).…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors

et al. 2022

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With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. Plasmodium falciparum, the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa. The P. falciparum proteasome is an attractive antimalarial target because its inhibition kills the parasite at multiple stages of its life cycle and restores artemisinin sensitivity in parasites that have become resistant through mutation in Kelch K13. Here, we detail our efforts to develop noncovalent, macrocyclic peptide malaria proteasome inhibitors, guided by structural analysis and pharmacokinetic properties, leading to a potent, species-selective, metabolically stable inhibitor.

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“…Macrocycle TDI5575 was developed using a strategy to covalently link the P2 and P4 phenyl groups of DPLG2 ( Fig 3 and Table 1 ) [ 46 ]. S2 and S4 binding pockets are partially exposed to solvent.…”

Section: Introductionmentioning

confidence: 99%

“…The co-crystal structure of Mtb20SOG with TDI5575 showed that the bulky 2-phenyl substituent on the pyrrolidinyl of the P3-Asn binds to the shallow but wide S3 pocket, affording strong species selectivity. Treating Mtb with TDI5575 led to the accumulation of Pup-tagged GFP and to death of nonreplicating Mtb under NO stress [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

Microbial proteasomes as drug targets

Zhang

Lin

2021

PLoS Pathog

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Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.

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Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome

Cited by 10 publications

References 48 publications

Structural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex

Structural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors

Microbial proteasomes as drug targets

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