The evolution of small molecule enzyme activators

Dow, Louise F.; Case, Alfie M.; Paustian, Megan P.; Pinkerton, Braeden R.; Simeon, Princess; Trippier, Paul C.

doi:10.1039/d3md00399j

RSC Med. Chem.

2023

DOI: 10.1039/d3md00399j

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The evolution of small molecule enzyme activators

Louise F. Dow,

Alfie M. Case,

Megan P. Paustian

et al.

Abstract: There is a myriad of enzymes within the body responsible for maintaining homeostasis by providing the means to convert substrates to products as and when required. Physiological enzymes are tightly...

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Cited by 5 publications

(1 citation statement)

References 296 publications

(509 reference statements)

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“…13 The development of small-molecule enzyme activator compounds is rapidly becoming a viable therapeutic discovery strategy for many diseases. 14,15 In our efforts to identify Nln activator compounds for stroke, we previously disclosed a peptidomimetic scaffold represented by Nln-10c and Nln-11a, 16 optimized from a dipeptide hit (HY) obtained from a high-throughput screen (Figure 1). 17 Both compounds possessed "drug-like" pharmacokinetic parameters, including brain penetration.…”

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confidence: 99%

Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability

Rahman,

Hadi Esfahani,

Zhang

et al. 2024

ACS Med. Chem. Lett.

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The peptidase neurolysin (Nln) has been validated as a potential target for developing therapeutics for ischemic stroke (IS). Overexpression of Nln in a mouse model of IS provides significant cerebroprotection, leading to reduced infarction size and edema volume. Pharmacological inhibition of Nln in the poststroke brain worsens neurological outcomes. A virtual screen identified dipeptide small-molecule activators of Nln. Optimization studies resulted in a class of peptidomimetic compounds with promising activity. However, these compounds still possessed an amide bond that compromised their stability in plasma and the brain. Herein, we report the synthesis and characterization of a series of amide bioisosteres based on our peptidomimetic leads. Imidazole-based bioisosteres afford scaffolds with increased potency to activate Nln combined with enhanced mouse plasma stability and significantly better brain permeability over the original dipeptide hits.

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mentioning

confidence: 99%

Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability

Rahman,

Hadi Esfahani,

Zhang

et al. 2024

ACS Med. Chem. Lett.

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Therapeutic development approaches to treat haploinsufficiency diseases: restoring protein levels

Evans,

Shyr,

Traynor

et al. 2024

Drug Discovery Today

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Unraveling the mechanism of small molecule induced activation of Staphylococcus aureus signal peptidase IB

Chen,

Fiedler,

Gronauer

et al. 2024

Commun Biol

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Staphylococcus aureus signal peptidase IB (SpsB) is an essential enzyme for protein secretion. While inhibition of its activity by small molecules is a well-precedented mechanism to kill bacteria, the mode of activation is however less understood. We here investigate the activation mechanism of a recently introduced activator, the antibiotic compound PK150, and demonstrate by combined experimental and Molecular Dynamics (MD) simulation studies a unique principle of enzyme stimulation. Mass spectrometric studies with an affinity-based probe of PK150 unravel the binding site of PK150 in SpsB which is used as a starting point for MD simulations. Our model shows the localization of the molecule in an allosteric pocket next to the active site which shields the catalytic dyad from excess water that destabilizes the catalytic geometry. This mechanism is validated by the placement of mutations aligning the binding pocket of PK150. While the mutants retain turnover of the SpsB substrate, no stimulation of activity is observed upon PK150 addition. Overall, our study elucidates a previously little investigated mechanism of enzyme activation and serves as a starting point for the development of future enzyme activators.

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The evolution of small molecule enzyme activators

Abstract: There is a myriad of enzymes within the body responsible for maintaining homeostasis by providing the means to convert substrates to products as and when required. Physiological enzymes are tightly...

Cited by 5 publications

References 296 publications

Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability

Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability

Therapeutic development approaches to treat haploinsufficiency diseases: restoring protein levels

Unraveling the mechanism of small molecule induced activation of Staphylococcus aureus signal peptidase IB

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