I-Thapsigargin (TG): I-Anti-cancer enokubakho kunye ne-Broad-spectrum Anti-viral Agent enokuthi isebenze ngokuchasene ne-SARS-CoV-2

I-agent ephuma kwisityalo, i-Thapsigargin (TG) isetyenziswe kumayeza esintu ixesha elide. I-TG ibonise izithembiso njengechiza elinokulwa nomhlaza ngenxa yepropathi yebhayoloji ukunqanda i-sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) impompo eyimfuneko ukuze iseli isebenze. I-prodrug yayo igqibe isigaba soku-1 solingo lwezonyango. Ngokwengxelo yophando yamva nje, i-TG ibonise ipropathi ebanzi ye-antiviral ngokuchasene noluhlu lweentsholongwane zabantu kulingo lwangaphambili. Iziphumo zibonisa ukuba i-TG inokusetyenziswa njenge-inhibitor ngokuchasene ne-SARS-CoV-2, inoveli coronavirus enoxanduva lwe-COVID-19.  

I-Thapsigargin (TG), isityalo esivela kwisityalo esiqhelekileyo i-Thapsia garganica (Apiaceae) nenzalelwane yaseMeditera. Isityalo siyingozi kakhulu ezinkomeni nasezigusheni kungoko sibizwa ngokuba ''ngumnqathe obulalayo''. I-resin ephuma kwesi sityalo isetyenziswe kumayeza esintu kwizifo ezahlukeneyo kangangeenkulungwane.  

Ipropathi ye-cytotoxic ye-thapsigargin ibangelwa ukukwazi ukuvimbela i-sarcoplasmic / endoplasmic reticulum i-Ca2 + ATPase (SERCA) impompo ngokwenza iiseli zingasebenzi. Oku kwenza i-TG yaba ngumgqatswa onokuthi anqande umhlaza ⁽¹⁾. Iprodrug yayo iMipsagargin igqibe isigaba soku-1 solingo lwezonyango kodwa akukho ziphumo zithunyelweyo okwangoku ⁽²⁾.  

Kumanqanaba angeyo-cytotoxic, i-thapsigargin ifunyaniswa inepropathi ye-antiviral ngokuchasene nentsholongwane ye-Influenza A kwiimodeli zezilwanyana. ⁽³⁾. Uphando olongezelelweyo lubonise ukuba i-TG isebenza kakhulu ngokuchasene nentsholongwane yokuphefumla ye-syncytial virus (RSV), i-community cold coronavirus OC43, SARS-selwe-2 kunye nentsholongwane yomkhuhlane A kwiiseli zomntu eziphambili, ngaloo ndlela yenza i-thapsigargin ibe yinto enokwenzeka uluhlu olubanzi i-anti-viral agent yonyango lwezifo zentsholongwane kubantu ⁽⁴⁾. Olu phuhliso lubonelela ngesixhobo esitsha sobuchule sokujongana ne-COVID-19 ebangelwa yintsholongwane ye-SARS-CoV-2 kwaye ibaluleke kakhulu xa kujongwa imeko enzima ethiwe thaca ngubhubhane. ^(4,5). Nangona kunjalo, kufuneka ingene kulingo lwezonyango olusisinyanzelo ukuze ihlangabezane nemigangatho yokhuseleko efunekayo kunye nokusebenza kakuhle, ngaphambi kokuba iqwalaselwe ukusetyenziswa kwayo ekunyangeni abaguli abosuleleke yi-COVID-19.   

Kwangoko, i-BX795 ibonise amandla njenge-arhente ye-antiviral ebanzi ukuze isetyenziswe ebantwini. ⁽⁶⁾. I-BX795 isebenza ngokuvimbela iprotheni kinase B (AKT) i-phosphorylation kunye ne-hyperphosphorylation elandelayo ye-4EBP1. Ibonise ipropathi ye-antiviral ngokuchasene ne-herpes simplex virus (HSV) kwaye ibonakaliswe ukucinezela iimpendulo ezivuthayo. ⁽⁷⁾. Nangona kunjalo, akukho lulingo lwekliniki lubonakala luqhubeka ukuze le arhente iqhubele phambili. Kutshanje, enye iarhente. I-diABZI (i-STING agonist) ibonise ipropathi ye-antiviral ngokuchasene nosulelo lwe-coronavirus ⁽⁸⁾.  

Ezi molekyuli zibonisa ithemba elithembisayo njengeearhente ezichasene nentsholongwane egazini kunyango lwe Covid-19. Nangona kunjalo, nganye kwezi kufuneka ingene kulingo lwezonyango olufunekayo ukubonisa ukhuseleko kunye nokusebenza kwayo phambi kokuba ivunywe ukuba isetyenziswe ebantwini njengeyeza. 

***

Iingxelo:  

1. Jaskulska A., Janecka AE., kunye no-Gach-Janczak K., 2020. I-Thapsigargin-Ukusuka kwi-Traditional Medicine ukuya kwi-Anticancer Drug. Int. J. Mol. Sci. 2021, 22(1), 4; Ipapashwe: 22 December 2020. DOI: https://doi.org/10.3390/ijms22010004 

2. I-ClinicalTrials.gov 2015. I-Dose-Escalation Phase 1 Study of G-202 (Mipsagargin) kwizigulane ezineeTumors eziPhezulu eziQinisekileyo. Isazisi seClinicalTrials.gov: NCT01056029. Iyafumaneka kwi https://clinicaltrials.gov/ct2/show/NCT01056029 Ifikeleleke nge-03 kaFebruwari 2021.  

3. Goulding LV., Yang J., et al 2020. I-Thapsigargin kwiNqanaba le-Non-Cytotoxic yenza i-Antiviral Host i-Antiviral Response eVimba i-Influenza i-Virus Replication. Iintsholongwane 2020, 12(10), 1093; Ipapashwe: 27 Septemba 2020. DOI: https://doi.org/10.3390/v12101093 

4. I-Al-Beltagi S., Preda CA., 2021. I-Thapsigargin Yi-Broad-Spectrum Inhibitor ye-Major Human Respiratory Virus: i-Coronavirus, iNtsholongwane yokuPhumeza i-Syncytial Virus kunye ne-Influenza A Virus. Iintsholongwane 2021, 13(2), 234. Ipapashwe: 3 February 2021. DOI: https://doi.org/10.3390/v13020234 

5. IYunivesithi yaseNottingham 2021. Iindaba-Izazinzulu zityhila unyango olunokubakho lwe-antiviral lwe-Covid-19. Ithunyelwe nge-03 kaFebruwari 2021. Iyafumaneka kwi-intanethi  https://www.nottingham.ac.uk/news/thapsigargin-covid-19 

6. Jaishankar et al. 2018. Umphumo ojoliswe kuyo we-BX795 uvimba uhlobo lwentsholongwane ye-herpes simplex 1 usulelo lweso. Iyeza leNzululwazi lokuGuqulela. 10(428). https://doi.org/10.1126/scitranslmed.aan5861 

7. Yu t., Wang ZW., et al 2020. I-kinase inhibitor BX795 icinezela impendulo yokuvuvukala nge-multiple kinases. I-Biochemical Pharmacology Volume 174, April 2020, 113797. Ipapashwe nge-10 kaJanuwari 2020. DOI: https://doi.org/10.1016/j.bcp.2020.113797 

8. Zhu Q., Zhang Y., 2021. Uthintelo losulelo lwe-coronavirus yi-agonist yokwenziwa ye-STING kwindlela yomoya yomntu. Antiviral Research Volume 187, March 2021, 105015. Ipapashwe 12 January 2021. DOI: https://doi.org/10.1016/j.antiviral.2021.105015 

***