Kaempferol as a therapeutic agent in Alzheimer’s disease: Evidence from preclinical studies

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 87, P. 101910 - 101910

Published: March 15, 2023

Language: Английский

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The evolution of small molecule enzyme activators

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 14(11), P. 2206 - 2230

Published: Jan. 1, 2023

There is a myriad of enzymes within the body responsible for maintaining homeostasis by providing means to convert substrates products as and when required. Physiological are tightly controlled many signaling pathways their subsequently control other pathways. Traditionally, most drug discovery efforts focus on identifying enzyme inhibitors, due upregulation being prevalent in diseases existence endogenous that can be modified afford inhibitor compounds. As downregulation reduction activators observed multiple diseases, identification small molecules with ability activate has recently entered medicinal chemistry toolbox chemical probes potential therapeutics an alternative intervene diseases. In this review we highlight progress made advancement non-kinase treating various disease states.

Language: Английский

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

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(4), P. 510 - 517

Published: March 29, 2024

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

Language: Английский

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Structural basis of divergent substrate recognition and inhibition of human neurolysin

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 8, 2024

A zinc metallopeptidase neurolysin (Nln) processes diverse bioactive peptides to regulate signaling in the mammalian nervous system. To understand how Nln interacts with various dissimilar sequences, we determined crystal structures of complex including dynorphins, angiotensin, neurotensin, and bradykinin. The show that binds these a large dumbbell-shaped interior cavity constricted at active site, making minimal structural changes accommodate different peptide sequences. also readily similar distinct registers, which can determine whether serves as substrate or competitive inhibitor. We analyzed activities binding toward forms dynorphin peptides, highlights promiscuous nature shows (1–13) potently inhibits activity while (1–8) is efficiently cleaved. Our work provides insights into broad specificity may aid future design small molecule modulators for Nln.

Language: Английский

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Discovery of the Next Generation of Non-peptidomimetic Neurolysin Activators with High Blood-Brain Barrier Permeability: a Pharmacokinetics Study in Healthy and Stroke Animals

Pharmaceutical Research, Journal Year: 2023, Volume and Issue: 40(11), P. 2747 - 2758

Published: Oct. 13, 2023

Language: Английский

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