Cystargolide-based amide and ester Pz analogues as proteasome inhibitors and anti-cancer agents

Viera, Carlos; Stevens, Bradley T.; Viera, Talysa; Zielinski, Cameron; Uranga, Lee A.; Rogelj, Snezna; Patidar, Praveen; Tello‐Aburto, Rodolfo

doi:10.1098/rsos.220358

“…ClpP and Clp ATP‐ases are currently being pursued as drug targets in several lead optimization programs based on natural, semisynthetic, and synthetic modulators [7,8a,22a–d] . Inhibition of the Clp protease is a promising anti‐virulence and anti‐mycobacterial strategy, while activation and dysregulation of ClpP have been shown to inhibit bacterial and tumour proliferation in preclinical and clinical studies, respectively [7,23] .…”

Section: Discussionmentioning

confidence: 99%

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active‐Site Inhibitor Cystargolide A

Illigmann,

Vielberg,

Lakemeyer

et al. 2023

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The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural β‐lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semisynthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti‐virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, and Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β‐lactones, the predominant class of ClpP inhibitors.

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Structure of Staphylococcus aureus ClpP Bound to the Covalent Active‐Site Inhibitor Cystargolide A

Illigmann,

Vielberg,

Lakemeyer

et al. 2023

Angew Chem Int Ed

3

0

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The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural β‐lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semisynthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti‐virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, and Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β‐lactones, the predominant class of ClpP inhibitors.

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Cryptic enzymatic assembly of peptides armed with β-lactone warheads

Xu,

Torri,

Cuesta-Hoyos

et al. 2024

Nat Chem Biol

5

0

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Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic warheads have proven to be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization of the pathways that nature deploys to assemble peptides with β-lactone warheads, which are potent proteasome inhibitors with promising anticancer activity. Warhead assembly involves a three-step cryptic methylation sequence, which is likely required to reduce unfavorable electrostatic interactions during the sterically demanding β-lactonization. Amide-bond synthetase and adenosine triphosphate (ATP)-grasp enzymes couple amino acids to the β-lactone warhead, generating the bioactive peptide products. After reconstituting the entire pathway to β-lactone peptides in vitro, we go on to deliver a diverse range of analogs through enzymatic cascade reactions. Our approach is more efficient and cleaner than the synthetic methods currently used to produce clinically important warhead-containing peptides.

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Cystargolide-based amide and ester Pz analogues as proteasome inhibitors and anti-cancer agents

Cited by 4 publications

References 33 publications

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active‐Site Inhibitor Cystargolide A

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active‐Site Inhibitor Cystargolide A

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active‐Site Inhibitor Cystargolide A

Cryptic enzymatic assembly of peptides armed with β-lactone warheads

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