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1kits (Ebipipa 10) .
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▎ Enzimba ya SS-31
Ensibuko: PubChem |
Omutendera: RXKF Ensengekera ya molekyu: C 32H 49N 9O5 Obuzito bwa molekyu: 639.8g/mol Ennamba ya CAS: 736992-21-5 PubChem CID: 11764719. Omuntu w’abantu Ebigambo ebifaanagana: Elamipretide |
▎ SS-31 Okunoonyereza
Ensibuko y’okunoonyereza eya SS-31 eri etya?
SS-31 ye tetrapeptide etabulwa mu mazzi, ewunya cationic, egenderera mitochondria (Sabbah HN, 2022). Ensengekera yaayo ey’enjawulo ey’eddagala egisobozesa okwanguyirwa okuyingira n’okubeera mu kitundu ekitono mu luwuzi lwa mitochondrial olw’omunda. Okusingira ddala, esobola okwesiba ku cardiolipin, ekitundu ekikulu eky’oluwuzi lwa mitochondrial olw’omunda, bwe kityo ne kikola ekikolwa kyayo eky’okulongoosa enkola ya mitochondrial.
Ensengekera eno ey’enjawulo ey’eddagala etuwa omusingi gw’okugikozesa mu kujjanjaba endwadde ez’enjawulo. Endwadde nnyingi zikwatagana n’obutakola bulungi bwa mitochondria, gamba nga Barth syndrome, okulemererwa kw’omutima, endwadde z’obusimu, n’ebirala Mitochondria zikola kinene nnyo mu kukola amaanyi g’obutoffaali, okulungamya okunyigirizibwa kw’okwokya, n’ebintu ebirala. Enkola ya mitochondria bw’ekosebwa, kiyinza okuvaako ebizibu ng’amaanyi g’obutoffaali obutamala, okweyongera kw’okunyigirizibwa kw’obusimu (oxidative stress), n’okuzimba obusimu (neuroinflammation), nga kino nakyo kivaako endwadde ez’enjawulo.
Okunoonyereza n’okukola SS-31 kugenderera okutunuulira endwadde zino ezeekuusa ku mitochondria, okukendeeza ku bubonero bw’endwadde nga tulongoosa enkola ya mitochondria n’okutumbula omutindo gw’obulamu bw’abalwadde n’omutindo gw’okuwangaala. Olw’okunoonyereza okw’obwegendereza okugenda mu maaso ku biology ya mitochondria, abantu bazze bategeera mpolampola obukulu bwa mitochondria mu kubeerawo n’okukula kw’endwadde.
Abanoonyereza bakizudde nti obutakola bulungi bwa mitochondrial bukwatagana nnyo n’enkola za pathophysiological ez’endwadde ez’enjawulo. Okugeza, mu ndwadde ezikendeeza ku busimu, waliwo ensonga nga obutakola bulungi mu mitochondria z’obusimu, okuzimba obusimu obutawona, okukuŋŋaanyizibwa kwa puloteyina ez’obutwa, n’okufa kw’obusimu [1] . Nga tannayingira kunoonyereza kwa bujjanjabi, SS-31 yakola okunoonyereza okunene nga tekunnabaawo. Okunoonyereza kuno kwalimu okugezesa okwakolebwa ku bikolwa by’obutoffaali n’ebikozesebwa mu bisolo okwekenneenya obukuumi, obulungi, n’obulungi bw’eddagala lino. Okugeza, mu kunoonyereza ku bulwadde bwa Barth, SS-31 yalaga obusobozi okulongoosa amangu mitochondrial bioenergetics ne morphology mu induced pluripotent stem cell models [2]..
Mu kunoonyereza ku ndwadde z’obusimu, SS-31 eraze ebikolwa eby’okukuuma obusimu mu bikolwa by’ebisolo ebingi, omuli okutumbula okussa kw’emitochondria, okuziyiza okuzimba kw’obusimu, n’okuziyiza okukuŋŋaanyizibwa kwa puloteyina ez’obutwa [1] . SS-31 yayingizibwa dda mu kunoonyereza okuwerako okukwata ku bitundu by’endwadde eby’enjawulo.
Mu kujjanjaba okulemererwa kw’omutima, okugezesebwa okwakolebwa mu ngeri ey’ekifuulannenge, okwafugibwa placebo kwalaga nti okufuyira SS-31 omulundi gumu tekirina bulabe era kigumiikiriza bulungi, era ddoozi ennene eya SS-31 esobola okulongoosa obuzito bw’omusuwa gwa kkono, ekiwagira omulimu gwayo oguyinza okukolebwa mu kujjanjaba okulemererwa kw’omutima [3]..
Enkola ki entongole ez’okukola kwa SS-31 mu bikolwa by’endwadde eby’enjawulo?
1. Enkola y’okukola mu muze gw’okusannyalala kw’omusaayi n’okuzibikira kwa bbaatule y’omusuwa
Mu nkola y’obuvune obuva ku ischemia-reperfusion injury (IRI) obuva ku hemorrhagic shock ne aortic balloon occlusion (REBOA), okwonooneka kwa mitochondria kukola kinene. SS-31 esobola okukendeeza ku bwetaavu bw’amazzi aga crystalloid n’okukuuma ensigo n’omutima. Okusingira ddala, esobola okukendeeza ku bungi bwa serum creatinine, troponin, ne interleukin-6, naye tekirina kye kikola ku bungi bwa plasma lactate obusembayo. SS-31 eyinza okukendeeza ku IRI nga ekuuma mitochondria, okuggulawo emikutu emipya egy’obujjanjabi eri abalwadde abatawaanyizibwa IRI oluvannyuma lw’okuvaamu omusaayi [4]..
2. Enkola y’okukola mu bulwadde bwa Barth syndrome
Obulwadde bwa Barth syndrome buzibu obutatera kulabika obukwatagana ne X obumanyiddwa nga cardiomyopathy, okunafuwa kw’ebinywa by’amagumba, okulwawo okukula, n’okukendeera kw’obusimu obuyitibwa cyclic neutropenia. SS-31 ye tetrapeptide etabulwa mu mazzi, ewunya cationic, mitochondria-targeted tetrapeptide esobola okuyingira mu luwuzi lwa mitochondria olw’ebweru n’ekwatagana ne cardiolipin. Kitumbula obulamu bw’obutoffaali nga kirongoosa okukola amaanyi n’okuziyiza okutondebwa okuyitiridde kw’ebika bya okisigyeni ebikola, bwe kityo ne kikendeeza ku situleesi y’okwokya. Mu butoffaali obusibuka obuyitibwa induced pluripotent stem cells obwa Barth syndrome n’endwadde endala ezikwatagana n’obuzaale ezimanyiddwa nga childhood cardiomyopathy, SS-31 esobola okulongoosa amangu mitochondrial bioenergetics ne morphology. Ebivudde mu kunoonyereza okungi biwagira enkozesa ya SS-31 ng’obujjanjabi obuyinza okuweebwa abalwadde abalina obulwadde bwa Barth, naddala mu mbeera nga obulwadde bw’emisuwa gy’omutima buzuuliddwa [2]..
3. Enkola y’okukola mu bulwadde bw’ekibumba obuyitibwa autosomal dominant polycystic kidney disease (ADPKD) .
Olubuto lutwalibwa ng’olwongera okukula kw’ebizimba mu bulwadde bw’ekibumba obuyitibwa autosomal dominant polycystic kidney disease (ADPKD). Wabula tolvaptan, eddagala lyokka eryakkirizibwa ekitongole kya FDA ku ADPKD enkuze, teriba kirungi ku balwadde ba ADPKD abali embuto olw’obulabe obuyinza okutuuka ku mwana ali mu lubuto. SS-31 ye tetrapeptide ekuuma mitochondria ezuuliddwa nti etereeza enkulaakulana y’obulwadde bw’ekibumba mu mbeba za Pkd1RC/RC ez’embuto, ate nga ekendeeza ku ERK1/2 phosphorylation n’okulongoosa okutondebwa kwa mitochondria supercomplexes. Okugatta ku ekyo, SS-31 esobola okusalako enseke n’amata g’amabeere, okulongoosa obulwadde bw’ekibumba obw’amaanyi obw’abaana abawere obuyitibwa polycystic kidney disease awatali bulabe bwonna obw’okuzaala oba obw’obulabe. Okunoonyereza kuno nga tekunnabaawo kuwagira okugezesebwa kw’obujjanjabi okuyinza okubaawo okwa SS-31 [5]..
4. Enkola y’okukola mu kulemererwa kw’omutima
Mu kulemererwa kw’omutima (HF), enkyukakyuka embi mu mitochondria zimanyiddwa nti zibaawo. SS-31 erina akakwate akalungi ku mitochondrial ne supercomplex emirimu gy’omutima gw’omuntu okulemererwa. Kiyinza okwongera nnyo ku oxygen flux, complex I ne complex IV activity, n’emirimu complex IV ekwatagana ne supercomplexes mu mitochondria z’omutima gw’omuntu ezinafuye, okulongoosa ennyo okulemererwa kw’emirimu gya mitochondria z’omuntu [6]..
Mu baana abalina obulwadde bw’omutima obuzaalibwa mu ventricle emu (SV CHD), ebiraga obujjanjabi bw’okusimbuliza omutima biraga nti waliwo obutakola bulungi bwa mitochondrial. SS-31 ye pentapeptide egenderera cardiolipin esobola okulongoosa enkolagana ya mitochondrial supercomplexes (complex I, III, IV). Mu mitima gy’abaana abalina SV CHD, SS-31 esobola okulongoosa emirimu gya complex I n’okussa okusingawo (MR), ekiraga nti okusinga ekola ekikolwa kyayo nga elongoosa mitochondrial supercomplexes [7]..
5. Enkola y’okukola mu bulwadde bwa sukaali obw’ekibumba
Mu nkola y’ebibe eya db/db eya sukaali ow’ekika eky’okubiri, obulwadde bwa sukaali obw’ekibumba (DKD) bukwatagana n’okukendeera kw’emiwendo gya superoxide mu kibumba n’omutima. Ekirungo ekikuuma mitochondria SS-31 (era ekimanyiddwa nga MTP-131, SS-31, oba Bendavia) kisobola okuziyiza ennyo okweyongera mu proteinuria, urinary H2O2, ne glomerular mesangial matrix accumulation mu db/db mice, era ne kikuuma ddala emitendera gy’okukola superoxide mu kibumba mu mbeba zino. SS-31 era esobola okukendeeza ku lysocardiolipin yonna ey’ekibumba n’ebibinja ebikulu ebya lysocardiolipin mu mbeba za db/db, n’okukuuma okwolesebwa kwa lysocardiolipin acyltransferase 1. Ebivuddemu bino biraga nti mu sukaali ow’ekika eky’okubiri, DKD ekwatagana n’okukendeera kw’emiwendo gya superoxide mu kibumba n’omutima, era SS-31 eyinza okukuuma DKD n’okukuuma emiwendo gya superoxide mu mubiri nga gitereeza okuddamu okukola kwa cardiolipin [8]..
Ekifaananyi ekiteeberezebwa kifunza ebikolwa eby’okukuuma obusimu ebya elamipretide ku kufuga omutindo gw’obusimu obuyitibwa neural mitochondria.
Ensibuko:PubMed [1] .
Biki ebikwatagana n’okukozesa SS-31?
Obulwadde bw’emisuwa gy’omutima mu bulwadde bwa Barth: Obulwadde bwa Barth bulwadde obutatera kulabika era obuyinza okutta omuntu obukwatagana ne X obumanyiddwa nga obulwadde bw’emisuwa gy’omutima, okunafuwa kw’ebinywa by’amagumba, okulwawo okukula, n’okukendeera kw’obusimu obuyitibwa cyclic neutropenia. Abalwadde balina emikisa mingi egy’okufa mu baana abawere era batera okufuna obulwadde bw’emisuwa gy’omutima obuwerekerwako okunafuwa ennyo kw’abaserikale b’omubiri. SS-31 eraga okusoomoozebwa n’emikisa gy’okujjanjaba obulwadde bw’emisuwa gy’omutima mu balwadde abalina obulwadde bwa Barth syndrome. Ebyavudde mu kunoonyereza okungi biwagira okugikozesa ng’obujjanjabi obuyinza okuweebwa abalwadde abalina obulwadde bwa Barth syndrome naddala nga kizuuliddwa nti obulwadde bw’emisuwa gy’omutima. Kiyinza okuba n’akakwate akawangaala ku kukulaakulana kw’obulwadde bw’emisuwa gy’omutima era mpolampola n’enzimba ne kikyusa okuddamu okukola kw’ekisenge kya kkono ekiremye ku mutendera gw’ensi yonna, ogw’obutoffaali, ne molekyu [2]..
Obulwadde bw’omutima obuzaalibwa mu ventricle emu:
Obulwadde bw’omutima obuzaalibwa bwe businga okubeera obulemu mu kuzaalibwa, era obulwadde bw’omutima obw’amaanyi obw’omu kisenge ekimu (single ventricle congenital heart disease) bwe businga okulaga okusimbuliza omutima gw’abaana abawere, ng’obujjanjabi butono nnyo mu kiseera kino. Kizuuliddwa nti waliwo obutakola bulungi bwa mitochondria mu mitima gy’abaana abalina obulwadde bw’omutima obuzaalibwa mu ventricle emu, era peptide SS-31 egenderera mitochondria esobola okulongoosa enkola ya mitochondria y’omutima. Okwongera okunoonyereza ku busobozi bw’eddagala lino okulongoosa enkola y’emisuwa gy’omutima n’okulwawo okugenda mu maaso kw’okusimbibwa kwetaagisa [7]..
Obulwadde bw’obusimu bw’amaaso obusikira mu Leber:
Okunoonyereza kwekenneenya obukuumi, okugumiikiriza, n’obulungi bw’okukozesa SS-31 ku mubiri mu kujjanjaba abalwadde abalina obulwadde bw’obusimu bw’amaaso obw’ensikirano obwa Leber. Ebivuddemu biraga nti SS-31 yali egumiikiriza bulungi, naye teyatuuka ku nkomerero y’obulungi bw’okulaba obusookerwako. Naye, okwekenneenya emirimu gy’okulaba mu kiseera ky’okugaziya eky’okuggulawo n’okwekenneenya okw’oluvannyuma kwalaga okulongoosa okuzzaamu amaanyi mu kukyama okwa wakati okw’ekifo ekirabika eky’omu makkati, ekyetaagisa okwongera okunoonyereza [9]..
Obulwadde bw’obusimu bw’amaaso obulumwa:
Kizuuliddwa nti SS-31 (MTP-131), tetrapeptide ya molekyu entono egenderera mitochondria, bw’ekozesebwa nga egattibwa wamu n’ekiziyiza ekizimba ekizimba etanercept, esobola okukola ng’ekikuuma obusimu eri obutoffaali bw’amaaso oluvannyuma lw’okulumwa obusimu bw’amaaso mu mbeba. Subcutaneous etanercept oba MTP-131 yokka n’okugatta kwazo byonna bisobola okwongera ku bulamu bw’obutoffaali bwa retina ganglion, naye tewali synergistic effect yalabibwa nga zikozesebwa nga zigatta [10]..
Obuvune bw’omugongo: SS-31 (SS-31) ye peptide ey’akawoowo akapya aka cationic peptide esobola okusala mu ddembe ekiziyiza omusaayi n’obwongo. Okunoonyereza kulaga nti SS-31 etumbula okuddamu okukola oluvannyuma lw’okulumwa omugongo nga eziyiza cPLA2-mediated autophagic damage, okuziyiza okweyongera mu lysosomal membrane permeability, n’okuziyiza pyroptosis, era erina omugaso oguyinza okukozesebwa mu bujjanjabi [11]..
Okuzimba kw’obusimu n’okukosa okutegeera:
Mu nvunza ezikaddiye, lipopolysaccharide esobola okuleeta okuzimba mu nkola n’okuzimba obusimu, ate SS-31 esobola okukozesebwa okujjanjaba. Okunoonyereza kulaga nti okuziyiza okuzimba obusimu bw’omubiri (hippocampal neuroinflammation) tekiyinza kukoma ku kukendeeza ku kuddamu kw’okuzimba mu hippocampus wabula n’okulongoosa enkola y’okuyungibwa kw’obwongo mu bitundu ebikwatagana ne hippocampus. Obujjanjabi obuziyiza okuzimba nga bukyali ne SS-31 bulina ekikolwa ekiwangaala ku kukendeeza ku buzibu bw’okuzimba obusimu obuleetebwa lipopolysaccharide [12]..
Obulwadde bw’ekibumba obuyitibwa autosomal dominant polycystic:
Olubuto lutwalibwa ng’olwongera okukula kw’ebizimba mu bulwadde bw’ekibumba obuyitibwa autosomal dominant polycystic kidney disease. Kizuuliddwa nti tetrapeptide ekuuma mitochondria SS-31 esobola okulongoosa enkulaakulana y’obulwadde bw’ekibumba mu mbeba za Pkd1^{RC/RC} ez’embuto, ate nga ekendeeza ku ERK1/2 phosphorylation n’okulongoosa okutondebwa kwa mitochondrial supercomplexes. SS-31 esobola okusalako enseke n’amata g’amabeere, okulongoosa obulwadde obw’amaanyi obw’ekibumba obuyitibwa infantile polycystic kidney disease awatali bulabe bwonna obw’okuzaala oba obw’obulabe [5]..
Endwadde ezikosa obusimu:
SS-31 ye mitochondria-targeted small molecule tetrapeptide eraga ebikolwa by’obujjanjabi n’obukuumi mu ndwadde ez’enjawulo ezikwatagana ne mitochondria. Mu ndwadde ezikendeeza ku busimu, SS-31 esobola okutumbula okussa kw’obusimu obuyitibwa mitochondrial, okukola ku butonde bw’obusimu obuyitibwa neuronal mitochondrial biogenesis okuyita mu mitochondrial biogenesis regulators ne translocator factors, okutumbula okuyungibwa kw’obusimu obuyitibwa mitochondrial fusion, okuziyiza mitochondrial fission, okwongera ku mitophagy, okukendeeza ku neuronal oxidative stress, neuroinflammation, n’okukuŋŋaanyizibwa kwa puloteyina ez’obutwa, okuziyiza obusimu obuyitibwa neuronal apoptosis, n’okutumbula amakubo g’obusimu obuwangaala. N’olwekyo, SS-31 eyinza okuziyiza okukulaakulana kw’endwadde z’obusimu ng’eyongera ku kussa kw’obusimu, okutondebwa kw’ebiramu, okuyungibwa, n’amakubo g’okuwangaala kw’obusimu, awamu n’okuziyiza okukutuka kw’obusimu, okunyigirizibwa okw’okwokya, okuzimba obusimu, okukuŋŋaanyizibwa kwa puloteyina ez’obutwa, n’okufa kw’obusimu [1]..
Sarcopenia: Kizuuliddwa nti wiiki 8 ez’obujjanjabi ne SS-31 zisobola okuzzaawo ekitundu enkyukakyuka ezeekuusa ku myaka mu protein phosphorylation mu binywa by’amagumba by’ebibe ebikazi ebikadde, ekikwatagana n’okulongoosa enkola y’ebinywa by’amagumba n’okuzzaawo enkyukakyuka mu protein S-glutathionylation [13]..
Nga eddagala erigendereddwamu mitochondria, SS-31 etuwa enkola ey’obuyiiya ey’okujjanjaba endwadde za mitochondria. Nga ekuuma ensengekera n’enkola ya mitochondria, eraga omugaso mu bujjanjabi mu ndwadde nga LHON ne Barth syndrome, naddala okulaga obulungi obw’amaanyi mu acute optic neuropathy. Kikola ku bujjanjabi ku ndwadde ez’enjawulo ezikwatagana n’obutakola bulungi mu mitochondria, gamba ng’okulemererwa kw’omutima n’endwadde z’obusimu, era kisobola okumalawo obubonero n’okulwawo okukulaakulana kw’obulwadde.
Ebikwata ku Muwandiisi
Ebintu ebyogeddwako waggulu byonna binoonyerezeddwako, birongooseddwa era ne bikung’aanyizibwa kkampuni ya Cocer Peptides.
Omuwandiisi wa Scientific Journal
Daneshgar N mumanyi wa maanyi mu by’ensoma, era omulimu gwe ogw’okusoma gukwatagana nnyo ne Yunivasite y’e Iowa ne Oregon State University. Ebitundu bye eby’okunoonyereza binene era bya buziba, nga bikwata ku misomo mingi ng’eby’abakadde n’eby’abakadde, enkola y’emisuwa n’omutima, eby’obulamu n’ebiramu ebya molekyu, obulamu bw’obutoffaali, ne kookolo. Mu by’obujjanjabi bw’abakadde n’abakadde, Daneshgar N yeewaddeyo okunoonyereza ku nkola z’ebiramu ez’okukaddiwa n’okuyingira mu nsonga ennungi ku ndwadde ezeekuusa ku kukaddiwa, ng’asuubira okutumbula omutindo gw’obulamu n’omutindo gw’obulamu bw’abakadde ng’ayita mu kunoonyereza.
Mu nsonga y’enkola y’emisuwa n’eby’omutima, akola okunoonyereza okw’obwegendereza ku ntandikwa y’endwadde, enkola y’okuzuula, n’obukodyo bw’okujjanjaba endwadde z’emisuwa, ekiyamba mu kuziyiza n’okujjanjaba endwadde z’emisuwa. Mu kitundu kya biochemistry ne molecular biology, essira aliteeka ku nsengeka, enkola, n’enkolagana ya biomolecules, okubikkula ebyama by’emirimu gy’obulamu ku mutendera gwa molekyu n’okuwa omusingi gw’enzikiriziganya okutegeera n’okujjanjaba endwadde. Mu by’obulamu bw’obutoffaali, Daneshgar N essira aliteeka ku nsengeka, enkola, n’amateeka g’emirimu gy’obulamu bw’obutoffaali, ng’asoma enkola enkulu nga okukyusa obubonero bw’obutoffaali n’okulungamya enzirukanya y’obutoffaali, n’awa obubonero obukulu okunoonyereza ku nkola y’obutoffaali bw’endwadde. Mu by’obujjanjabi bwa kkansa, yeewaddeyo okunoonyereza ku nkola y’okubeerawo n’okukula kw’ebizimba, wamu n’okuzuula n’okujjanjaba ebizimba, okunoonyereza ku bubonero obuzuula amangu n’ebigendererwa ebipya eby’obujjanjabi eri ebizimba, okuleeta essuubi eppya eri abalwadde b’ebizimba. Daneshgar N awandiikiddwa mu kiwandiiko ekijuliziddwa [5].
