Medicinal Chemistry Optimization of Acyldepsipeptides of the Enopeptin Class Antibiotics

Hinzen, Berthold; Raddatz, Siegfried; Paulsen, Holger; Lampe, Thomas; Schumacher, Andreas; Häbich, Dieter; Hellwig, Veronica; Benet‐Buchholz, Jordi; Endermann, Rainer; Labischinski, Harald; Brötz‐Oesterhelt, Heike

doi:10.1002/cmdc.200600055

Cited by 81 publications

(152 citation statements)

References 14 publications

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“…Z-Leu-Leu-Nva-CHO was purchased from Boston Biochem. ADEPs and N-E-2-heptenoyldifluorophenylalanine methyl ester were synthesized as described (30,31,33,37 (12) was followed by increases in fluorescence (excitation, 320 nm; emission, 420 nm). GFP-ssrA degradation was assayed by decreases in fluorescence (excitation, 380 nm; emission, 511 nm) in the presence of 2.5 mM ATP (Sigma) and a regeneration system consisting of 16 mM creatine phosphate (MP Biomedicals) and 0.32 mg/mL creatine phosphokinase (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Schmitz

Carney

Sello

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

201

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Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein-substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis.AAA+ proteases | allosteric coupling | pathogen drug target

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Section: Methodsmentioning

confidence: 99%

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Schmitz

Carney

Sello

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

201

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“…39 Although ADEPs are promising leads for drug candidates, they have unfavorable pharmacological properties including poor water solubility, rapid systemic clearance and chemical instability. 51,60 Following the discovery of ADEPs' mode of action, a medicinal chemistry SAR program was launched by Bayer AG, to develop a more stable and potent derivative of ADEP. This effort resulted in the development of ADEP4, a highly potent ADEP1 derivative with three important modifications: Phe is replaced by 3,5-difluorophenylalanine, which is thought to form H bonds with ClpP, the acyl polyene is replaced by an α,β-unsaturated hexenoyl tail to improve stability and N-MeAla is replaced by pipecolate, which increases ADEP's rigidity.…”

Section: Clpp Activatorsmentioning

confidence: 99%

“…This effort resulted in the development of ADEP4, a highly potent ADEP1 derivative with three important modifications: Phe is replaced by 3,5-difluorophenylalanine, which is thought to form H bonds with ClpP, the acyl polyene is replaced by an α,β-unsaturated hexenoyl tail to improve stability and N-MeAla is replaced by pipecolate, which increases ADEP's rigidity. 60 Activity of ADEP4 was further improved by Carney et al 61 by replacing Ser with Allo-Thr and Pip with 4-MePip to further rigidify ADEP. By quantifying hydrogen-deuterium exchange rates using 1 H NMR, rigidification of the ADEP molecule was shown to strengthen the transannular H bonds, thereby reducing the entropic costs of binding to ClpP.…”

Section: Clpp Activatorsmentioning

confidence: 99%

Bacterial proteases, untapped antimicrobial drug targets

2016

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Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

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“…A total synthesis was described in 1997. [82] Researchers at Bayer have revised the initial structure of A54556A, [83] and have determined the mechanism of action. [84] The conformation has also been studied by NMR in DMSO solution.…”

Section: Enopeptinsmentioning

confidence: 99%

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

Obrecht¹,

Robinson²,

Bernardini

et al. 2009

CMC

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O (2009Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics AbstractNovel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents. Abstract:Novel therapeutic strategies are urgently needed for the treatment of serious

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Medicinal Chemistry Optimization of Acyldepsipeptides of the Enopeptin Class Antibiotics

Cited by 81 publications

References 14 publications

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Bacterial proteases, untapped antimicrobial drug targets

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

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