Recent Advances in the Development of Elastase Inhibitors

Donarska, Beata; Łączkowski, Krzysztof Z.

doi:10.4155/fmc-2020-0163

Cited by 15 publications

(13 citation statements)

References 20 publications

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“…However, in pathological conditions, excessive expression of elastase can damage vascular composition, induce inflammation, and promote virus or bacteria infection. 11 Once SARS-CoV-2 infects the host cell, systemic immune overactivation ( Figure 1 ) is especially noteworthy in severely ill patients. At the first stage of immune response, elastase released from neutrophils plays a key role.…”

Section: Introductionmentioning

confidence: 99%

Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and In Vivo Biological Evaluation for Acute Lung Injury

Cui

Zhang

et al. 2022

J. Med. Chem.

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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most common complications in COVID-19. Elastase has been recognized as an important target to prevent ALI/ARDS in the patient of COVID-19. Cyclotheonellazole A (CTL-A) is a natural macrocyclic peptide reported to be a potent elastase inhibitor. Herein, we completed the first total synthesis of CTL-A in 24 linear steps. The key reactions include three-component MAC reactions and two late-stage oxidations. We also provided seven CTL-A analogues and elucidated preliminary structure–activity relationships. The in vivo ALI mouse model further suggested that CTL-A alleviated acute lung injury with reductions in lung edema and pathological deterioration, which is better than sivelestat, one approved elastase inhibitor. The activity of CTL-A against elastase, along with its cellular safety and well-established synthetic route, warrants further investigation of CTL-A as a candidate against COVID-19 pathogeneses.

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Section: Introductionmentioning

confidence: 99%

Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and In Vivo Biological Evaluation for Acute Lung Injury

Cui

Zhang

et al. 2022

J. Med. Chem.

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“…It exhibits a specific activity against serine protease elastase, proteinase K and chymotrypsin; it is able to inhibit HNE, with an IC 50 value of 23 nM [ 29 , 31 ]. Its structure is characterized by a cyclic depsipeptide core composed of 19 residues, including the 3-amino-6-hydroxy-2-piperidone (Ahp) [ 9 , 31 ]. A low quantity of Lyngbyastatin 7 can be isolated from the natural source.…”

Section: Cyclic Peptides Derived From Bacteria As Elastase Inhibitorsmentioning

confidence: 99%

“…Neutrophils, a large population of leukocytes, play an important role in the regulation of the innate and adaptive immune responses, quickly achieving the inflammation/infection site [ 8 ]. During the degranulation process, neutrophils release human neutrophil elastase (HNE) ( Figure 1 ), a glycoprotein composed of 218 amino acids, through extracellular neutrophil traps (NETs) [ 8 , 9 ]. NETs are composed of decondensed chromatin, neutrophil elastase and other enzymes [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…NETs are composed of decondensed chromatin, neutrophil elastase and other enzymes [ 8 ]. HNE is a serine protease belonging to the chymotripsin family that is produced in the bone marrow during the stage of promyelocytes [ 9 ]. Neutrophil serine proteases are involved in inflammation and the immune response [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…This enzyme has a catalytic site of three amino acids, called the catalytic triade: Asp102, His57 and Ser195. The mechanism of action of serine proteases, which includes neutrophil elastase, is illustrated in Scheme 1 ; when the target ligand achieves the enzymatic catalytic site, a proton transfer happens among the three amino acids, causing an increased nucleophile activity of Ser195 with a concomitant peptide bond cleavage [ 9 , 11 ]. In regular conditions, a balance between human neutrophil elastase activity and its endogenous inhibitors (e.g., elafin, serpins, α1-antitrypsin and secretory leukocyte proteinase inhibitor) is guaranteed, while the imbalance between elastase activity and its endogenous inhibitors can cause a variety of illnesses, such as chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome and pulmonary fibrosis [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview

Marinaccio

Stefanucci

Scioli

et al. 2022

IJMS

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Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural lead compounds. Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC50 values in a range from nM to μM values, thus representing an interesting starting point for the further development of potent bioactive compounds on human elastase enzymes.

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Desing, synthesis, and characterization of some 5,6‐dichloro benzimidazole derivatives with investigation of their antioxidant and elastase inhibitory activities

Albay,

Tekbaş

2023

Journal of Heterocyclic Chem

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Starting from the 5,6‐dichloro‐2‐phenyl‐1H‐benzimidazole, new benzimidazole derivatives having schiff base, carbothioamide, thiadiazole, and triazole moiety were synthesized and characterized. Synthesized compounds were characterized by NMR spectroscopy, mass spectroscopy and elemental analyses techniques. Antioxidant and elastase inhibitory activities of compounds were also investigated. The inhibitory effects on elastase activity of the synthesized molecules were analyzed spectrophotometrically. The antioxidant activities of molecules were investigated by both methods as DPPH (1,1‐diphenyl‐2‐picrylhydrazyl) free radical scavenging activity and iron reducing power capacities. All synthesized compounds showed good antioxidant and elastase inhibitory activity. Compound 2 showed the highest elastase inhibition. Compound 3 and compound 2 showed the highest antioxidant activity by DPPH method, and iron reducing power method, respectively.

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Recent Advances in the Development of Elastase Inhibitors

Cited by 15 publications

References 20 publications

Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and In Vivo Biological Evaluation for Acute Lung Injury

Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and In Vivo Biological Evaluation for Acute Lung Injury

Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview

Desing, synthesis, and characterization of some 5,6‐dichloro benzimidazole derivatives with investigation of their antioxidant and elastase inhibitory activities

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