Synthesis, biological evaluation and molecular modeling of pseudo-peptides based statine as inhibitors for human tissue kallikrein 5

Hoelz, Lucas Villas Bôas; Zorzanelli, Bruna C.; Azevedo, Pedro H.R. de A.; Passos, Silvia G.; Souza, Lucas R. de; Zani, Marcelo B.; Pinheiro, Sérgio; Puzer, Luciano; Dias, Luiza R.S.; Muri, Estela M.F.

doi:10.1016/j.ejmech.2016.01.060

Cited by 11 publications

(5 citation statements)

References 41 publications

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“…Whereas statin pseudopeptides are well‐known inhibitors of aspartyl‐proteases, by mimicking the tetrahedral transition state of the peptide cleavage reaction, small pseudopeptides 3 incorporating a statin residue in their sequence have been recently reported to inhibit the serine protease KLK5 in the submicromolar range (Fig. ) . Based on molecular docking experiments, the authors proposed that the methylene and the benzyl groups of the statin residue occupied the S1 and the S2 pocket of the enzyme, respectively.…”

Section: Nonphysiological Inhibitorsmentioning

confidence: 99%

“…13). 117 Based on molecular docking experiments, the authors proposed that the methylene and the benzyl groups of the statin residue occupied the S1 and the S2 pocket of the enzyme, respectively. Key H-bonds interactions could occur with several residues of KLK5 (namely Cys191, Gln192, Asp194, Ser214, and the catalytic Ser195).…”

Section: F I G U R E 1 4 Examples Of Covalent Inhibitors Of Klksmentioning

confidence: 99%

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Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

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Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition.

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Section: Nonphysiological Inhibitorsmentioning

confidence: 99%

Section: F I G U R E 1 4 Examples Of Covalent Inhibitors Of Klksmentioning

confidence: 99%

Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…HCl) 43 , by employing the classical N-(3-dimethylaminopropyl) N'-ethylcarbodiimide/1-hydroxy-benzotriazole/ N-methylmorpholine (EDC/HOBt/NMM) protocol (Fig. 2) 18,44 .…”

Section: Chemistrymentioning

confidence: 99%

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro)

Azevedo,

Camargo,

Constant

et al. 2024

Sci Rep

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COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.

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“…Several groups have generated peptide-based KLK5 and KLK7 inhibitors by altering the specificity loop of the sunflower trypsin inhibitor (SFTI-1). − The most potent SFTI-1-based KLK5 and KLK7 inhibitors have K i ’s of 0.34 and 0.14 nM, respectively. , A potent KLK7 inhibitor was also developed based on a cyclic depsipeptide, but its intricate, natural-product-based structure makes its preparation rather complex . A range of small molecule inhibitors were identified, with the best KLK5 inhibitors having medium nanomolar potency − and the best KLK7 inhibitors having low nanomolar potency . A challenge with small molecule inhibitors has been the achievement of sufficient selectivity over the various trypsin and chymotrypsin-like serine proteases present in humans, several of which have important functions.…”

Section: Introductionmentioning

confidence: 99%

Phage Display Selected Cyclic Peptide Inhibitors of Kallikrein-Related Peptidases 5 and 7 and Their In Vivo Delivery to the Skin

et al. 2022

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Kallikrein-related peptidases 5 (KLK5) and 7 (KLK7) are serine proteases with homeostatic functions in the epidermis that play a critical role in Netherton syndrome (NS), a rare yet life-threatening genetic disorder that currently lacks specific treatment. Previous research suggests that controlling KLKs could lead to the development of NS therapies, but existing synthetic inhibitors have limitations. Herein, we used phage display to screen libraries comprising more than 100 billion different cyclic peptides and found selective, high-affinity inhibitors of KLK5 (K i = 2.2 ± 0.1 nM) and KLK7 (K i = 16 ± 4 nM). By eliminating protease-prone sites and conjugating the inhibitors to an albumin-binding peptide, we enhanced the inhibitor stability and prolonged the elimination half-life to around 5 h in mice. In tissue sections taken from mice, a fluorescently labeled peptide was detected in the epidermis, suggesting that the inhibitors can reach the KLKs upon systemic delivery and should be suited to control deregulated protease activity in NS.

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Synthesis, biological evaluation and molecular modeling of pseudo-peptides based statine as inhibitors for human tissue kallikrein 5

Cited by 11 publications

References 41 publications

Inhibitors of kallikrein‐related peptidases: An overview

Inhibitors of kallikrein‐related peptidases: An overview

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro)

Phage Display Selected Cyclic Peptide Inhibitors of Kallikrein-Related Peptidases 5 and 7 and Their In Vivo Delivery to the Skin

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