Phthalocyanines as molecular scaffolds to block disease-associated protein aggregation (

CLAUDIO O. FERNANDEZ

ACCOUNTS OF CHEMICAL RESEARCH

AMER CHEMICAL SOC

Lugar: Washington; Año: 2016

0001-4842

8CONSPECTUS:Theaggregationofproteinsintotoxicconformationsplaysacriticalrole9inthedevelopmentofdifferentneurodegenerativediseasessuchasAlzheimer?sdisease10(AD),Parkinson?sdisease(PD),andCreutzfled−Jakob?sdisease(CJD).Thesedisorders11shareacommonpathologicalmechanismthatinvolvestheformationofaggregatedprotein12speciesincludingtoxicoligomersandamyloidfibrils.Theaggregationofalpha-synuclein13(αS)inPDandtheamyloidbetapeptide(Aβ)andtauproteininADresultsinneuronal14deathanddiseaseonset.InthecaseofCJD,themisfoldingofthephysiologicalprion15protein(PrP)inducesachainreactionthatresultsinaccumulationofparticlesthatelicit16braindamage.Currently,thereisnopreventivetherapyforthesediseasesandtheavailable17therapeuticapproachesarebasedonthetreatmentofthesymptomsratherthanthe18underlyingcausesofthedisease.Accordingly,theaggregationpathwayoftheseproteins19representsausefultargetfortherapeuticintervention.Therefore,understandingthe20mechanismofamyloidformationanditsinhibitionisofhighclinicalimportance.The21designofsmallmoleculesthatefficientlyinhibittheaggregationprocessand/orneutralizeitsassociatedtoxicityconstitutesa22promisingtoolforthedevelopmentoftherapeuticstrategiesagainstthesedisorders.Inthisaccounts,wediscusscurrent23knowledgeontheanti-amyloidactivityofphthalocyaninesandtheirpotentialuseasdrugcandidatesinneurodegeneration.24ThesetetrapyrroliccompoundsmodulatetheamyloidassemblyofαS,tau,Aβ,andthePrPinvitro,andprotectcellsfromthe25toxiceffectsofamyloidaggregates.Inaddition,inscrapie-infectedmice,thesecompoundsshowedimportantprophylactic26antiscrapieproperties.Thestructuralbasisfortheinhibitoryeffectofphthalocyaninesonamyloidfilamentassemblyrelieson27specificπ−πinteractionsbetweenthearomaticringsystemofthesemoleculesandaromaticresiduesintheamyloidogenic28proteins.Analysisofthestructure−activityrelationshipinphthalocyaninesrevealedthattheiranti-amyloidactivityishighlydependentonthetypeofthemetalioncoordinatedtothetetrapyrrolicsystembutisnotsensitivetothenumberofperipheralchargedsubstituents.Thetendencyofphthalocyaninestooligomerize(self-association)viaaromaticinteractionscorrelatespreciselywiththeirbindingcapabilitiestotargetproteinsand,moreimportantly,determinestheirefficiencyasanti-amyloidagents.Theabilitytoblockdifferenttypesofdisease-associatedproteinaggregationraisesthepossibilitythatthesecyclictetrapyrrolecompoundshaveacommonmechanismofactiontoimpairtheformationofavarietyofpathologicalaggregates.Becausethestructuralandmolecularbasisfortheanti-amyloideffectsofthesemoleculesisstartingtoemerge,combinedeffortsfromthefieldsofstructural,cellular,andanimalbiologywillresultcriticalfortherationaldesignanddiscoveryofnewdrugsforthetreatmentofamyloidrelatedneurologicaldisorders.