Gelatinaasi-inhibiittorien kehittelystä MMP-2 ja MMP-9-inhibitio. Thiirane

http://pubs.rsc.org/en/content/articlelanding/2014/ra/c3ra46402d#!divAbstract

New clicked thiirane derivatives as gelatinase inhibitors: the relevance of the P1′ segment

B. Fabre,^a  K. Filipiak,^ab  C. Coderch,^a  J. M. Zapico,^a  Rodrigo J. Carbajo,^c  Anne K. Schott,^c  Antonio Pineda-Lucena,^c  B. de Pascual-Teresa*^a  and  A. Ramos*^a 

Author affiliations

Abstract

Gelatinases (MMP-2 and MMP-9), a subfamily of Matrix Metalloproteinases (MMPs), are involved in several pathologies and especially in cancer. Thiirane is a latent-zinc binding group used for the design of potent inhibitors of gelatinases. Here we report a new family of thiirane inhibitors, obtained by click chemistry. Thus, an azide fragment containing the thiirane group was connected to several lipophilic alkynes, which were designed to interact with the S1′ pocket of the two gelatinases. Our hit compound (2f) displayed submicromolar inhibition of MMP-2 (IC₅₀ = 0.62 μM). Computational studies have been used to compare the binding mode of compound 2f in MMP-2 with the reference thiirane inhibitor (SB-3CT), allowing us to discuss the relevance of the P1′ segment in order to maximize potency.

Supplementary files

• Supplementary information PDF (2391K)

Publication details

The article was received on 04 Nov 2013, accepted on 01 Apr 2014 and first published on 03 Apr 2014

Article type: Paper

DOI: 10.1039/C3RA46402D

Citation: RSC Adv., 2014,4, 17726-17735

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Anti-proteaasi-proteaasi tasapaino hengitysteissä

Esimerkkinä kystinen fibroosi:

https://www.researchgate.net/figure/The-importance-of-the-balance-between-proteases-and-antiproteases-in-CF-airways-The_fig1_44579199

The main source of protease activity in the CF lung is thought to be activated neutrophils, however, the role of proteases derived from other cell sources, such as mononuclear and epithelial cells, as well as exogenously derived bacterial proteases may also play a vital role in mediating destruction of the lung as seen in CF (as illustrated in Fig. 1). The main emphasis of this review will be to address the role of these endogenous and exogenous proteases and describe past, present and future developments in the search for an efficient antiprotease therapy in CF.

https://www.researchgate.net/profile/Cliff_Taggart/publication/44579199/figure/fig1/AS:203132643614727@1425442004177/The-importance-of-the-balance-between-proteases-and-antiproteases-in-CF-airways-The.png




The release of proteolytic enzymes during the inflammatory response has enormous potential to exacerbate and prolong inflammation causing numerous deleterious effects such as lung tissue destruction and reduced bacterial clearance.

To counteract this, the airways are equipped with a highly regulated antiprotease shield to dampen and control excessive proteolytic activity. The protease-antiprotease imbalance hypothesis of chronic neutrophil-mediated lung disease contends that this imbalance, or overwhelming of the natural antiprotease defence mechanisms, determines pulmonary phenotype [31].

 Several CF studies have correlated protease lung burden with disease severity and have shown an inverse relationship to the status of the antiprotease defence shield [7, 32-34].

The function of the airway antiprotease defence system is to inhibit the activity of cognate proteases thereby preventing potentially damaging degradation of host tissue (Fig. 1).

The primary antiproteases of the airway are AAT, secretory leucoprotease inhibitor (SLPI), elafin, TIMPs and cystatins [31, 35-38]. The primary protease targets of AAT, SLPI and elafin are the serine proteases, NE, proteinase 3 and cathepsin G, all of which are released by activated neutrophils [30, 31, 35, 36].

MMP-12- inhibittoori

Muistiin:
http://www.merckmillipore.com/SE/en/product/MMP-12-Inhibitor-MMP408-CAS-1258003-93-8-Calbiochem,EMD_BIO-444291?ReferrerURL=https%3A%2F%2Fwww.google.se%2F

Synonyms: (S)-2-(8-(Methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid

Date of issue:

16.11.2014

Version:

1.0

Company

EMD Millipore Corporation | 290 Concord Road, Billerica, MA 018

21, United

States of America | General Inquiries: +1-978-715-4321 | Monday

to Friday, 9:00

AM to 4:00 PM Eastern Time (GMT-5)

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oute Industrielle

de la Hardt, Molsheim 67120, Fr

ance | General Inquiries: +39 (0

) 33 90 46 90 00

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MT+1)

Emergency telephone

number

800-424-9300 CHEMTREC (USA)

+1-703-527-3887 CHEMTREC (International)

24 Hours/day; 7 Days/week

Catalogue No.:

444291

Product name:

MMP-12 Inhibitor, MMP408

REACH Registration

Number:

A registration number is not available for this substance as the substance

or its use are exempted from registration according to Article2 REACH

Regulation (EC) No 1907/2006, the annual tonnage does not require a

registration or the registration is envisaged for a later registration deadline.

This item is not a hazardous substance and does not contain hazardous ingredients, substances with European Community workplace exposure limits or substances of v

ery high concern (SVHC) above their respective disclosure limits. Hence a safety data sheet is not required according to Regulation(EC) No. 1907/2006 (REACH) and also not available in this case....

MMP klusterin aktivaatiossa plasmiini merkitsevä.

Plasminergisen systeemin tehtävänä on  normalisoida kehoa sen jälkeen, kun on ilmentynyt fibrinogeenistä fibriiniä, jota pitäisi hajoittaa. Samalla plasmiini  useassa tapauksessa  joutuu aktivoimaan avuksi MMP-klusterin, jotta  suuresta hyytymästä päästään eroon  ja kudoksia voidaan uudistaa.

Mistä syystä siten  kehon koagulaatiojärjestelmä  aktivoituu ja trombiini alkaa pilkkoa  fibrinogeenistä fibriiniä  ja vaikutaa  loputla  palautumatonta  stabiilia fibriiniä?
 Siihen on tiestysti paljon syitäja  niihin on  suurin osa  tieteellisestä artikkeleista reologian alalta keskittynytkin.

Tromboosin estämiseen tavataan käyttää milloin  aspiriinia, milloin  marevan tyyppistä antikoagulanttia , milloin muita   strategioita , kuten trombosyyttien estäjiä.
Mutta keholla on myös oma järjestelmänsä, jolla se aivan jatkuvasti hoitaa  negatiivisen antikoagulaation   ja järjestelmän pitäisi  normaalissa kehossa toimia.  Siinä trombiinin ilmenemä  aktivoi veressä normaalisti  kiertävää  C-proteiinia ja  aktivoitu C-proteiini aPC toimii  koagulaatiokaskadin rauhoittajana.

 Mutta jos käytetään  suuria määriä aspiriinia  tai marevania,  C-proteiinia ei saada aktivoitumaan antikoagulantiksi, joten joudutaan  pilleri pillerin jälkeen säätämään  lopulta koko järjestelmää  sen sijaan että luottaisiin kehon normaaliin  koagulatiiviseen tasapainoon.

Mitä se normaali tasapaino käsittää?  Eräs tärkeä koagulaatiotekijä on aktiivi kalsiumjoni. (Tekijä FIV)
 Jota kalsiumjoni pysyisi  normaalipuitteissa ja kertyisi  varastoihinsa kuten luustoon,   todellakin tarvitaan tehokasta liikuntaa.
Jos liikunta puuttuu, on miltei mahdoton  ilman lääkkeitä selvitä koagulaatiotasapainon hoidosta ja samalla vielä luusto purkaa kalsiumia.
Jos haluaa  säilyttää normaalin koagulaatio-järjestelmänsä kannattaa kohtalaisen tai runsaan  liikunnan lisäksi  käyttää  K1-vitamiinipitoista ravintoa, kuten vihreitä vihanneksia ja kasvisöljyjä, jolloin  saa edellytyksiä  negatiivisen kogulaatiokontrollin jäsenten posttranslationaaliseen  muokkautumiseen funktionaaliseen muotoon.  Tämä voisi  "pinnan alla" näkymättömissä  pitää  reologista tasapainoa sellaisessa tilassa, että  ei muodostuisi  siinä määrin  sulamatonta fibriiniä, että plasminerginen järjestelmä aktivoituu ja  jopa aktivoi MMP-järjestelmän.

 Normaalisti MMP-järjestelmä on  hyvin  vähäisesti aktivoituneena.  Vain tarvittessa jossain paikallisesti se vaikuttaa  uudistelemassa solukalvojen extrasellulaarista materiaalia- se hajoittaa monin spesifisin tekijin vanhat materiaalit, jota uutta pääsee muodostumaan.

Jotta riehahtanutta  MMP-järjestelmää saa rauhoittumaan  täytyy katsoa syntyjä syviä aivan fibriinin  muodostumiseen asti.  Tämä on hyvin  yksinkertaistettu selitys.

 MMP-järjestelmän rauhoittamisessa ei ole eduksi käyttää  antitromboottisia lääkkeitä kuten ASA ja  antikoagulanttia vaikka lyhyellä tähätimellä ne  estävät fibriiniä muodostaumasta.
MMP  on hyvin monimutkainen järjestelmä eikä sille ole olemassa vielä mitään erityisiä  rauhoittavia lääkkeitä, estäjiä. ne eivät vähene  ASA tai antikoagulanttilääkityksestä.

Nykyään vielä kartoitetaan, miten paljon järjestelmä riehuu erilaisissa tiloissa.

Sellaisen liikunnan , joka ei ledeeraa, riko  kudoksia  (aiheuta kudosrikkoja),  ei varinaisesti pitäisi  aktivoida MMP-järjestelmää ylimäärin.

Tässä  lähinnä korostaisin  kudoksille aivan  perustavasti tärkeitä  olosuhteita:  ravintosuositukset  ovat sitä linjaa, kasvisten osuutta vuosi vuodelta korostetaan enemmän ja se samalla stabiloi  Kvitamiinin saannin hieman korkeammalle tasolle, mitä ennen näitä suosituksia.  Suosituksissa on myös sellaisia öljyjä, jotka antavat K1-vitamiinia.  Tämä on hidas tie  korjata  villiintynyttä MMP-klusteritoimintaa ja toivottavasti  tapahtuu jotain palautumista - siis  MMP-järjestelmän  palautumista  inaktiiviin tilaan.

Tämä on uusi kartta joka on ilmeentynyt koagulaatiokaskadin ja fibrinolyyttisen kaskadin  vierelle, eikä  kaikki vuorovaikutukset ole millään tavalla  varmoja  nuolia kartalla vielä. Lisätekijä on TIMP-kartta, MMP-kudosinhibiittorit , jotka näyttävät jo  riehuvan  syöpätutkimusalan karttojen puolella. nekin ovat yllättäen osoitatneet pahat puolensa, eikä nekään ole  mitenkään helposti lääkkeellisesti säädeltäviä.

Alun perin saataa koko tämä ihmeellisen  hyvä kaskadisekvessi mennä pieleen vain pelkästä liikunnan puutteesta ja joistain  elintapatekijöistä.  Pelkkä  puolen  tunnin lisäliikunta päivää kohti voisi olla  avain  oikeaan suuntaan johtavalle ovelle.

Matrixmetalloproteinaasit keuhkofibroosissa (IPF)

https://www.ncbi.nlm.nih.gov/pubmed/26121236

Am J Respir Cell Mol Biol. 2015 Nov;53(5):585-600. doi: 10.1165/rcmb.2015-0020TR.

Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis.

Craig VJ^1,2, Zhang L¹, Hagood JS^3,4, Owen CA^1,5

Abstract

Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF.

KEYWORDS:

fibrosis; idiopathic pulmonary fibrosis; interstitial lung disease; lung; matrix metalloproteinase

PMID:

26121236

PMCID:

PMC4742954

DOI:

10.1165/rcmb.2015-0020TR

[Indexed for MEDLINE]

Free PMC Article

Clinical Relevance

In this Translational Review, we describe the molecular and cell biology of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases, and review the evidence that links MMPs to idiopathic pulmonary fibrosis (IPF), the cellular sources of MMPs, and the mechanisms involved. Although initial studies of randomized clinical trials for nonselective MMP inhibitors as new therapies for cancer produced disappointing results, since then, newer approaches to target metalloproteinases more selectively have been developed for other diseases. We have included a discussion of the advantages (and potential limitations) of these new therapeutic approaches targeting MMPs and their potential as therapeutics for IPF.

Idiopathic Pulmonary Fibrosis

In the United States, approximately 50,000 patients are newly diagnosed with idiopathic pulmonary fibrosis (IPF) each year. The median survival of patients with IPF is only 3–5 years (1). Although numerous medical therapies have been evaluated in patients with IPF, the only therapies that slow the progression of this disease, pirfenidone (2) and nintedanib (3), are associated with side effects and are not fully effective at reducing mortality. Thus, there is an urgent need to identify novel therapeutic targets for IPF. Herein, we review the evidence linking members of the matrix metalloproteinase (MMP) family to the pathogenesis of IPF, identify knowledge gaps in the field of MMPs and IPF, and discuss potential approaches to target MMPs as novel therapeutics for IPF.

IPF is characterized by the deposition of excessive amounts of extracellular matrix (ECM) proteins in the lungs, thereby replacing the normal architecture of the lung. IPF is the most common type of idiopathic interstitial pneumonia, and is characterized pathologically by the pattern of usual interstitial pneumonitis. Although the etiology of IPF is still unclear, several pathogenic mechanisms have been implicated in its development, including aberrant repair of injured epithelium, fibroblast activation, epithelial-to-mesenchymal transition (EMT), collagen deposition, and immune cell dysfunction. MMPs are expressed by most of the cellular culprits and pathologic processes implicated in IPF pathogenesis.

MMPs

MMPs are zinc-dependent endopeptidases that, together, degrade all components of the ECM. Consequently, it was initially thought that MMPs would limit lung fibrosis by degrading ECM proteins in the lung. However, recent studies have implicated MMPs in regulating the activities of proteins other than ECM proteins, including mediators of inflammation, latent growth factors, antifibrotic growth factors, and cleaving cell surface molecules and receptors. However, most studies of MMP-deficient mice in pulmonary fibrosis (PF) models have shown the opposite—that MMPs promote pulmonary fibrotic responses to injury.

MMP Structure

MMPs are multidomain proteins (Figure 1). The signal peptide at the amino terminus targets the protein to the cell’s secretory pathway. The propeptide domain, containing the highly conserved cysteine switch motif, PRCGXPD, is cleaved during activation of the latent proenzyme by yet-to-be identified peptidases. The catalytic domain contains the highly conserved Zn²⁺-binding motif, HEXXHXXGXXH, in which the three histidines (H) bind to the active site zinc, and the nucleophilic glutamate (E) attacks the substrate’s peptide bond. The proline-rich hinge domain connects the catalytic domain to the C-terminal domain with a flexible segment of up to 75 residues. The carboxyterminal hemopexin-like domain regulates substrate binding and specificity. Some MMPs contain additional domans
.... kts. jatko  linkistä!

Mikä toimisi MMP klusterin inhibiittorina?

Biol Res Nurs. 2010 Apr;11(4):336-44. doi: 10.1177/1099800409346333. Epub 2009 Dec 22.

The role of doxycycline as a matrix metalloproteinase inhibitor for the treatment of chronic wounds.

Stechmiller J¹, Cowan L, Schultz G

Abstract

Many chronic wounds fail to heal with conventional therapy, resulting in disability and impaired quality of life. New technologies using recombinant growth factors, autologous growth factors, or bioengineered skin-tissue substitutes have been shown to be effective, but these treatments are costly. An effective, low-cost treatment to improve healing of chronic wounds is needed. The molecular environment of chronic wounds, like many other chronic inflammatory diseases, contains abnormally high levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL]-1beta]) and matrix metalloproteinases (MMPs), which impair normal wound healing. In animal models and clinical studies of ulcerative diseases, doxycycline, an inexpensive and Food and Drug Administration (FDA)-approved antibiotic, appears to inhibit members of the MMP superfamily like MMPs and TNF-alpha-converting enzyme (TACE). This article provides an overview of the roles of MMPs and intrinsic tissue inhibitors of metalloproteinases (TIMPs) in wound healing and the damaging effects of chronically elevated levels of MMPSs in chronic wounds. It also explores the use of topical doxycycline, a synthetic MMP inhibitor (MMPI), to enhance healing of chronic wounds.

Proteaasi-antiproteaasi-epätasapaino keuhkofibroosissa

https://www.ncbi.nlm.nih.gov/pubmed/29518524

Matrix Biol. 2018 Mar 5. pii: S0945-053X(17)30471-7. doi: 10.1016/j.matbio.2018.03.001. [Epub ahead of print]

The impaired proteases and anti-proteases balance in Idiopathic Pulmonary Fibrosis.

Menou A¹, Duitman J¹, Crestani B².Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a devastating chronic, progressive and irreversible disease that remains refractory to current therapies.

Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the development of pulmonary fibrosis since decades. Coagulation signalling deregulation, which influences several key inflammatory and fibro-proliferative responses, is also essential in IPF pathogenesis, and a growing body of evidence indicates that Protease-Activated Receptors (PARs) inhibition in IPF may be promising for future evaluation.

Therefore, proteases and anti-proteases aroused great biomedical interest over the past years, owing to the identification of their potential roles in lung fibrosis. During these last decades, numerous other proteases and anti-proteases have been studied in lung fibrosis, such as matriptase, Human airway trypsin-like protease (HAT), Hepatocyte growth factor activator (HGFA)/HGFA activator inhibitor (HAI) system, Plasminogen activator inhibitor (PAI)-1, Protease nexine (PN)-1, cathepsins, calpains, and cystatin C.

 Herein, we provide a general overview of the proteases and anti-proteases unbalance during lung fibrogenesis and explore potential therapeutics for IPF.

KEYWORDS:

Anti-protease; Cysteine protease; Idiopathic Pulmonary Fibrosis; Matrix metalloproteinase; Serine protease

PMID:

29518524

DOI:

10.1016/j.matbio.2018.03.001

Outline

1. Highlights
2. Abstract
3. Keywords
4. Idiopathic Pulmonary Fibrosis (IPF)
5. Pro- and anti-fibrotic lung proteases and anti-proteases deregulation in IPF
   • Matrix metalloproteinases (MMPs) and their cognate inhibitors
     • MMPs
     • TIMPs
   • Cysteine proteases and their cognate inhibitors
     • Cysteine proteases cathepsins, ATG4B, and calpains
     • Cystatin C
   • Serine proteases and their cognate inhibitors
     • Coagulation serine proteases
     • Type II transmembrane serine proteases (TTSPs)
     • The HGFA-HAI imbalance in IPF
     • Serine proteases inhibitors: plasminogen activator inhibitor-1 (PAI-1) and protease nexin-1 (PN-1) serpins
6. Therapeutic targeting of proteases/anti-proteases for IPF
7. Future directions
8. Conflicts of interest
9. Funding sources
10. References