Abstract
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.
Highlights
Elastic fibres compose an essential part of the extracellular matrix of connective tissue, where they allow its reversible and repetitive deformation
Each elastic fibre is mainly constituted by an amorphous core of elastin, which occupies more than 90% of the fibre, surrounded by an external envelope of microfibrils [1,2]
A huge variety of fibrillinbinding proteins occurs for the assembly of elastic fibres [3], which play an important role in ensuring mechanical resilience, durability and cell interactivity within tissues [4]
Summary
Elastic fibres compose an essential part of the extracellular matrix of connective tissue, where they allow its reversible and repetitive deformation. Betw eHlaNsEtaissdeepaoscitteidvaistyan aacntidve eintzsymeenidn othge eaznuorouphsiliicnghrainbulietsoorfspo(lyem.gor.,pheolnaufcilenar, serpi neutrophils This enzyme has a catalytic site of three amino acids, called the catalytic setrciardee:toArspy10l2e, uHiks5o7cayndteSepr1r95o.tTehienmaescehainnishmiobfiatcotiro)n oifssegriuneaprraotneatseees,dw,hiwchhile t eilnacslutdaesseneuatcrotpivhiil teylastaasne,dis iiltlussterantedd oingSechnemoeu1s; wihnehn ithbeittaorgrest licgaannd accahiuevsees thae varie enzymatic catalytic site, a proton transfer happens among the three amino acids, causing an chinrcroeanseicd nuocblesotprhuilecatcitviveitypofuSlemr19o5 nwaithrya codnciosmeaitasnet,peapctiduetbeonlducnleagvagine [j9u,1r1y]., acu syInnredgruolamr coendaitniodns,pauballmanocenbaetrwyeefnibhurmoasnisne[u1tr2op,1h3il ]e.laIsttashe aacstivriteycaenndtiltsyenb- een h dogenous inhibitors (e.g., elafin, serpins, α1-antitrypsin and secretory leukocyte proteinase trinohpibhitoirl) ies lgausartaansteeed,iwnhhiliebthiteoimrsbalcanocue bldetwbeeen eulassteasde acttoivittyraenadtitsaecnudotgeenoruesspirat (AinhRibDitoSrs) ccaan ucasueseda vbayrieCtyOofVillnIDess-e1s,9suicnhfaescchtiroonnic,obbsutrtuctthiveeiprulemfofneacrtyidviseeauses,e is y acute lung injury, acute respiratory distress syndrome and pulmonary fibrosis [12,13]. Both compounds inhibit HNE in a dose-dependent manner, but ShSPI exihnihbiibtsitaHmNoEreinefafedcotisvee-daecptievnitdyenthtamnaSninveelre, sbtautt aSthSthPeI seaxmhiebictsonacemnotrraetieofnfe.cStihvSePaIcaticvtsity wtithhana Sniovne-lceostmatpaettitthiveesianmhiebcitoionncemntercahtiaonni.smShaSgPaIinacsttsewlaistthasae,ndoins-pcloamyipnegtiativKei vinahluibeitoiof n 12m.6enchMa,naisnmd iatgsaeiqnustileiblarsituamse,ddisisspoclaiaytiinognacoKni svtaalnute(KofD1) 2to.6HnMNE, ainsd4.i2ts×e1q0u−i8l;ibfuriruthmerdmisosroec,iaShtSioPnI schonowstasnath(KugDe) stotaHbiNlitEy iasft4e.r2 c×o-1in0c−u8b; afutirotnhewrmithorheu, mShaSnPpI lsahsomwasoavheru4g8e hst[a1b2i]l.ity after co-incubation with human plasma over 48 h [12]
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