Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters.

ABSTRACT: Studies were performed to investigate the prohormone/proprotein convertase (PC)-inhibitory properties of chemical constituents of the medicinally active plant Andrographis paniculata (AP; from the family Acanthaceae), also known as 'King of Bitters'. Among the individual components tested against the clinically important convertases, furin and PC1, neoandrographolide (a C3 O-glucoside derivative of the major constituent andrographolide) exhibited the highest inhibitory action with an IC50 of 53.5 microM against furin. The data further revealed that although andrographolide, the major bitter principle of AP, exhibited a relatively small enzyme inhibition (IC50=1.0 mM and Ki=200 microM against furin), upon succinoylation, its inhibitory action against the above convertases was enhanced significantly with a Ki in the low micromolar range (<30 microM), suggesting that a specific structural modification of the andrographolide skeleton may be exploited to develop a new class of non-peptide inhibitors of PCs. When tested against PC7, these succinoylated derivatives of andrographolide also displayed strong inhibitory action, with Ki values again in the low micromolar range. This potentially interesting observation may be attributed to the reported anti-HIV property of 14-dehydroandrographolide succinic acid monoester (DASM). It is suggested here that DASM, by virtue of this protease inhibitory property, possibly acts by suppressing the proteolytic cleavage of envelope glycoprotein gp160 of HIV, which is known to be PC-mediated, particularly by furin and PC7.

SUBMITTER: Basak A

PROVIDER: S-EPMC1220031 | biostudies-other | 1999 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics.

Project description:Furin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer, and metastasis. Furin and related furin-like PCs cleave their substrates at characteristic multibasic consensus sequences, preferentially after an arginine residue. By incorporating decarboxylated arginine mimetics in the P1 position of substrate analogue peptidic inhibitors, we could identify highly potent furin inhibitors. The most potent compound, phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (15), inhibits furin with a K(i) value of 0.81 nM and has also comparable affinity to other PCs like PC1/3, PACE4, and PC5/6, whereas PC2 and PC7 or trypsin-like serine proteases were poorly affected. In fowl plague virus (influenza A, H7N1)-infected MDCK cells, inhibitor 15 inhibited proteolytic hemagglutinin cleavage and was able to reduce virus propagation in a long-term infection test. Molecular modeling revealed several key interactions of the 4-amidinobenzylamide residue in the S1 pocket of furin contributing to the excellent affinity of these inhibitors.

| S-EPMC2834293 | biostudies-literature

Substrate cleavage analysis of furin and related proprotein convertases. A comparative study.

Project description:We present the data and the technology, a combination of which allows us to determine the identity of proprotein convertases (PCs) related to the processing of specific protein targets including viral and bacterial pathogens. Our results, which support and extend the data of other laboratories, are required for the design of effective inhibitors of PCs because, in general, an inhibitor design starts with a specific substrate. Seven proteinases of the human PC family cleave the multibasic motifs R-X-(R/K/X)-R downward arrow and, as a result, transform proproteins, including those from pathogens, into biologically active proteins and peptides. The precise cleavage preferences of PCs have not been known in sufficient detail; hence we were unable to determine the relative importance of the individual PCs in infectious diseases, thus making the design of specific inhibitors exceedingly difficult. To determine the cleavage preferences of PCs in more detail, we evaluated the relative efficiency of furin, PC2, PC4, PC5/6, PC7, and PACE4 in cleaving over 100 decapeptide sequences representing the R-X-(R/K/X)-R downward arrow motifs of human, bacterial, and viral proteins. Our computer analysis of the data and the follow-on cleavage analysis of the selected full-length proteins corroborated our initial results thus allowing us to determine the cleavage preferences of the PCs and to suggest which PCs are promising drug targets in infectious diseases. Our results also suggest that pathogens, including anthrax PA83 and the avian influenza A H5N1 (bird flu) hemagglutinin precursor, evolved to be as sensitive to PC proteolysis as the most sensitive normal human proteins.

| S-EPMC2475709 | biostudies-literature

The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases.

Project description:A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly during morphogenesis or extracellularly after egress and during entry in order to produce mature virions activated for infection. Although viruses also take advantage of other proteases, it is when some viruses become reactive with PCs that they may develop high pathogenicity. Besides reacting with furin, some viruses may also react with the PCs of the other specificity group constituted by PC4/PC5/PACE4/PC7. The targeting of PCs for inhibition may result in a useful strategy to treat infections with some highly pathogenic viruses. A wide variety of PC inhibitors have been developed and tested for their antiviral activity in cell-based assays.

| S-EPMC6784293 | biostudies-literature

Differential gene expression of Andrographis paniculata and andrographolide enriched andrographis paniculata extract in liver cells

Project description:Andrographis paniculata Nees and its major compound andrographolide is known to exhibit a pleothera of activities. Active component enriched extracts are known to provide various beneficial effects, and therefore it was interesting to investigate whether increased amount of major compound alters gene expression. To acheive this, HePG2 cells treated with Andrographis paniculata extract (AP) and andrographolide enriched –extract (AP20) were subjected to microarray analysis to check their effect on global gene expression.

2018-11-06 | GSE74769 | GEO

Andrographis paniculata proteome

Project description:Andrographis paniculata (AP) is a medicinal herb used to treat infectious diseases. The medicinal properties are due to presence of andrographolide and other secondary metabolites synthesized via mevalonic acid (MVA) and methyl erythritol phosphate (MEP) pathways. To increase the andrographolide content plants were treated with 50µM Jasmonic acid (JA) for one week. HPLC analysis revealed that one fold increase in the andrographolide content compared to control. To study the signal mechanism underlying in the stress response, samples were subjected to Q-TOF-LC-MS/MS analysis. JA influences the expression of MVA and MEP enzymes in treated (22 enzymes) than in untreated (3 enzymes). We found total 3308 proteins in control and 3994 in elicited sample in which 1393 were commonly found in both. The differential expression revealed 621 proteins were down-regulated and 201 proteins were up regulated. The functional annotation involved 40 metabolic processes where post translational modifications was highly up regulated in treated (5.7%). The total proteome of A.paniculata was reported for the first time. The comparison of elicited and non elicited (control) samples revealed that the elicitation is an integrated process which release variety of bioactive compounds to defend itself from variety of pathogens. The Knowledge obtained from this scrutiny, JA dependent stress adaptive response is likely to have industrial and agricultural impact. It creates a hope towards future for the development of eco-friendly ways of managing pests and tapping into a largely unexplored treasure of plant-derived bioactive metabolites for human use. Particularly in this plant, it is useful for the production of medicines to cure different kinds of diseases and disorders.

2020-01-13 | PXD010674 | Pride

OFF-State-Specific Inhibition of the Proprotein Convertase Furin.

Project description:The pro-protein convertase furin is a highly specific serine protease involved in the proteolytic maturation of many proteins in the secretory pathway. It also activates surface proteins of many viruses including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furin inhibitors effectively suppress viral replication and thus are promising antiviral therapeutics with broad application potential. Polybasic substrate-like ligands typically trigger conformational changes shifting furin's active site cleft from the OFF-state to the ON-state. Here, we solved the X-ray structures of furin in complex with four different arginine mimetic compounds with reduced basicity. These guanylhydrazone-based inhibitor complexes showed for the first time an active site-directed binding mode to furin's OFF-state conformation. The compounds undergo unique interactions within the S1 pocket, largely different compared to substrate-like ligands. A second binding site was identified at the S4/S5 pocket of furin. Crystallography-based titration experiments confirmed the S1 site as the primary binding pocket. We also tested the proprotein convertases PC5/6 and PC7 for inhibition by guanylhydrazones and found an up to 7-fold lower potency for PC7. Interestingly, the observed differences in the Ki values correlated with the sequence conservation of the PCs at the allosteric sodium binding site. Therefore, OFF-state-specific targeting of furin can serve as a valuable strategy for structure-based development of PC-selective small-molecule inhibitors.

| S-EPMC8453481 | biostudies-literature

Hepatic proprotein convertases modulate HDL metabolism.

Project description:The risk of atherosclerosis is inversely associated with plasma levels of high-density lipoprotein cholesterol (HDL-C). However, HDL metabolism is incompletely understood, and there are few effective approaches to modulate HDL-C levels. Here we show that inhibition in the liver of the classical proprotein convertases (PCs), but not the atypical PCs S1P and PCSK9, decreases plasma HDL-C levels. This metabolic effect of hepatic PCs is critically dependent on expression of endothelial lipase (EL), an enzyme that directly hydrolyzes HDL phospholipids and promotes its catabolism. Hepatic PCs reduce EL function through direct inactivating cleavage of EL as well as through activating cleavage of angiopoietin-like protein 3 (ANGPTL3), an endogenous inhibitor of EL. Thus, inhibition of hepatic PCs results in increased EL activity, leading to reduced HDL-C as well as impaired reverse cholesterol transport. The hepatic PC-ANGPTL3-EL-HDL pathway is therefore a novel mechanism controlling HDL metabolism and cholesterol homeostasis.

| S-EPMC2565575 | biostudies-literature