Antifungal Drug Pipeline

Vazhinji vevarwere vedu vanotoziva nezvekuwedzera kudiwa kwemishonga mitsva yeantifungal; marapirwo ezvirwere zvefungal senge aspergillosis ane zvisingakwanisi. Muchetura, kusangana kwezvinodhaka-zvinodhaka, kuramba, uye dosing inyaya dzese dzinogona kuomesa kurapa; saka, iyo nzira yekurapa yakawanda yatinayo, isu tinowana mukana wakakwana wekurapa wevarwere. 

Kugadzira antifungal mishonga kwakaoma nekuda kwekufanana kwehupenyu pakati pevanhu nefungi; isu tinogovana akawanda emhando dzebiological nzira sefungi, kugadzira nyaya mukugadzira yakachengeteka antifungals. Kugadzira mishonga mitsva yeantifungal, vaongorori vanofanirwa kutarisa mashandisiro avangaita mamwe misiyano yatinayo.

Pazasi pane kupatsanurwa kwevasiri a ichangobva kuburitswa wongororo iyo yakatarisa mishonga minomwe yeantifungal parizvino iri mumatanho akasiyana ekukura. Ruzhinji rwevatsva antifungals vanga vari mitsva yemishonga yekare, asi iyo inokurukurwa muongororo iyi ine nzira itsva dzekuita uye dzakasiyana dosing regimens, saka, kana ikabvumidzwa, mishonga iyi inogona kupa tariro mune ramangwana risiri kure. mazwi ekurapa.

Rezafungin

Rezafungin parizvino iri muchikamu chechitatu chebudiriro. Iyo inhengo yekirasi ye echinocandin yemishonga, kusanganisira micafungin uye caspofungin; Echinocandins inoshanda nekudzivisa fungal cell wall chikamu chakakosha kune homeostasis.

Rezafungin yakagadziridzwa kuti ichengetedze zvikomborero zveechinocandin zvakatangira; apo ichivandudza pharmacokinetic yayo uye pharmacodynamic maitiro kuti iite yakasarudzika, yakareba-inobata, yakagadzikana kurapa inobvumira vhiki nevhiki intravenous pane kutonga kwezuva nezuva, inogona kuwedzera nzira dzekurapa mukugadzirisa echinocandin kuramba.

Fosmanogepix

Fosmanogepix inozivikanwa seyekutanga-mu-kirasi mushonga (saka yekutanga yerudzi rwayo antifungal) inovharira kugadzirwa kwekomisheni yakakosha yakakosha pakuvakwa kwemadziro emadziro uye kuzvidzora. Kuvhara kugadzirwa kwekomboni iyi kunonetesa madziro esero zvekuti sero harichakwanisa kutapurira mamwe maseru kana kunzvenga immune system. Parizvino iri muChikamu chechipiri chekuedza kwekliniki uye iri kuratidza migumisiro inovimbisa mumuromo uye intravenous kurapwa kweakawanda invasive fungal infections, kuratidzira kushanda mumishonga yakawanda isingagadziriswi uye zvimwe zvirwere zvakaoma kurapa.

Olorifim

Olorifim inowira pasi pekirasi nyowani yemishonga inorwisa fungal inonzi orotomides. Iyo orotomides ine yakasarudzika nzira yekuita, yakasarudzika yakanangana neiyo enzyme yakakosha mupyrimidine biosynthesis. Pyrimidine imorekuru rakakosha muDNA, RNA, sero madziro uye phospholipid synthesis, sero regulation, uye kugadzirwa kweprotein, saka kana Olorofim yakananga iyi enzyme, inokanganisa zvakanyanya fungi. Nehurombo, Olorifim haina kuwanda, uye inongouraya fungus shoma - zvine musoro, Aspergillus, uye fungus inokonzera valley fever (inokanganisa uropi), Coccidioides. Kubva payakawanikwa, yakafambira mberi kuburikidza nezvidzidzo zvepre-kiriniki uye chikamu chekutanga chekuyedzwa kwevanhu uye pari zvino chiri kuenderera mberi chikamu chechipiri chekuedza kwekliniki kuedza kushandiswa kwayo nemuromo uye mutsinga.

Ibrexafungerp

Ibrexafungerp ndiyo yekutanga yekirasi nyowani yeantifungals inonzi Triterpenoids. Ibrexafungerp inotarisa chinhu chimwe chakakosha chefungal cell wall iyo echinocandins inoita, asi ine chimiro chakasiyana zvachose, ichiita kuti ive yakasimba uye inoreva kuti inogona kupiwa nemuromo; kusiyanisa Ibrexafungerp kubva kune matatu aripo echinocandins (caspofungin, micafungin, andulafungin), iyo inogona kupiwa chete intravenously kuderedza kushandiswa kwavo kuvarwere vari muchipatara uye avo vane inwelling venous access.

Kune maviri arikuenderera chikamu 3 miedzo yebrexafungerp. Chidzidzo chekunyoresa zvakanyanya kusvika parizvino chidzidzo cheFURI, chinoongorora kushanda uye kuchengetedzeka kweIbrexafungerp pakati pevarwere vane hutachiona hwakanyanya hwefungal uye vasingateereri kana kushivirira kune akajairwa antifungal agents. Mushonga wemukanwa uchangobva kubvumidzwa neUSA's Food and Drug Administration (FDA) yekurapa vulvovaginal candidiasis (VVC).

Oteseconazole

Oteseconazole ndiyo yekutanga yeakawanda tetrazole agents akagadzirwa nechinangwa chekusarudza kukuru, zvishoma zvinokonzerwa nemigumisiro, uye kuvandudzwa kwekushanda kana zvichienzaniswa neazoles aripo iye zvino. Oteseconazole yakagadzirirwa kusunga zvakasimba kune enzyme inonzi cytochrome P450. Patakakurukura fungidziro yekare uye vanhu vakafanana, cytochrome P450 ndeimwe yezvakafanana. Masero evanhu ane marudzi akasiyana-siyana e cytochrome P450, ayo anokonzera mabasa akawanda anokosha emagetsi. Nokudaro, kana azole antifungal agents inhibit cytochrome P450 yevanhu, mhedzisiro inogona kuva yakashata. Asi, kusiyana nemamwe azole antifungals, Oteseconazole chete inhibits the fungal cytochrome p450- kwete munhu mumwe nokuda kwayo affinity nokuda chipfuro enzyme (cytochrome P450) mukuru. Izvi zvinofanirwa kureva kudyidzana kwezvinodhaka-zvinodhaka uye kushomeka kwehupfu.

Oteseconazole iri muchikamu chechitatu chebudiriro uye parizvino iri pasi peFDA inotariswa kuti ibvumidzwe kurapa inodzokororwa vulvovaginal candidiasis. 

Encochleated Amphotericin B

Vazhinji vevarwere vedu vanenge vatoziva nezveAmphotericin B, yanga iripo kubva kuma1950s. Amphotericin B inowira pasi pekirasi yemishonga inonzi Polyenes- kirasi yekare yemishonga inorwisa fungal iripo. Vanouraya fungi nekusunga kune ergosterol iyo inoshanda kuchengetedza sero membrane kuperera. Mushonga unoshanda nekubvisa ergosterol, ichikonzera maburi mu membrane yesero, ichiita kuti ibude zvekutadza kukundikana. Asi, polyenes zvakare anodyidzana necholesterol mumasero emunhu membranes, zvichireva kuti ane huturu hwakakosha. Encochleated Amphotericin B yakagadziridzwa kudzivirira iyi yakakosha chepfu - chinyorwa chayo lipid nanocrystal dhizaini inobvumira kuendesa zvinodhaka zvakananga kune ane hutachiona, kudzivirira muviri kubva pakufumurwa kusingakoshi - uye inogona kupihwa nemuromo, inogona kuderedza kugara muchipatara.

Encochleated Amphotericin B parizvino iri muzvikamu 1 & 2 zvebudiriro, saka padiki kure. Zvakadaro, inovimbisa kugona kwemushonga wemukanwa uine zvishoma, kana zviripo, zvehumwe huturu hweamphotericin B.         

ATI-2307

ATI-2307 iri mumatanho ekutanga ebudiriro uye mushonga mutsva weantifungal une nzira yakasarudzika yekuita. ATI-2307 inhibits mitochondrial function (mitochondria zvimiro zviri mukati memasero anoshandura chikafu kuita simba), zvichideredza kugadzirwa kweATP (adenosine triphosphate), inova iyo molecule inotakura simba, zvichitungamira mukudzivirirwa kwekukura.

Sezvambotaurwa, ATI-2307 ichiri mumatanho ekutanga. Zvakadaro, vaongorori vakapedza zvidzidzo zvekiriniki zveChikamu 1 zvakaratidza kuti zvakatenderwa muvanhu pane zvinotarisirwa kurapa dhamo. Saka, basa rekiriniki reATI-2307 harina kujeka; zvisinei, basa rayo rakafara mu vitro rinopesana nemhomho yefungal pathogens inokosha, kusanganisira yakawanda-inopikisa zvinodhaka zvipenyu, inogona kushandura kuita basa rinokosha remusanganiswa uyu, kunyanya kune zvirwere zvefungal nekuda kwezvipembenene zvinopikisa zvinodhaka zvakadai seAzole-resistant Aspergillus marudzi.

 

Tariro iri kumberi: Novel antifungal kurapwa mukusimudzira

Ongororo yakaburitswa nguva pfupi yadarika inotsanangura maantifungals matsva ari mupombi anopa tariro yeramangwana.

Mishonga mitsva inotsanangurwa muongororo ine nzira dzinoverengeka dzekuita kukunda kuramba, uye mamwe anopa maumbirwo matsva anopa mabhenefiti akasiyana pamusoro peazvino marapirwo ekuvandudza maprofile ekuchengetedza uye kuderedza kusangana. Semuenzaniso, Rezafungin yakaratidza chiitiko ichipokana Aspergillus mhando uye yakaderedza chiropa chehutu, kupinda zviri nani uye njodzi shoma yekuramba.

Pfupiso yemaitiro echiito, kuwanda kwechiitiko uye zvinotarisirwa mabhenefiti zvinopihwa mubepa raunogona kuwana pane Aspergillus Website. Vanyori vakagadzirawo mufananidzo wakakura weiyo nyowani antifungals uye basa ravo kuitira kuti mapeji asara aonekwe nyore. Aspergillus mhando dzakasimbiswa nebhokisi rebhuruu.

Zvinokurudzira zvikuru kuona kuti akati wandei emakomponi ane simba rekupikisa Aspergillus mhando uye kuti Ibrexafungerp, komisheni inokanganisa fungal cell wall, ine basa rinopesana nevanoverengeka Aspergillus mhando uye iri muchikamu chechitatu chekiriniki miedzo.

Izvo zvinogona kubatsira zvemushonga uyu zvinosanganisira:

  • Oral uye IV kuumbwa
  • Active pakurwisana nemhando dzinopikisa
  • Kupinda kurinani (IAC)
  • Kudyidzana kwezvinodhaka nezvinodhaka zvishoma

Pamusoro pezvo, olorofim, VL2397 uye ABA zvese zvine chekuita nekupikisa Aspergillus mhando uye dziri mumatanho akasiyana-siyana ekuyedzwa kwekiriniki. Muzvose, kune tariro yechokwadi pamusoro pedenga

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