Sistematični pregled in napoved toksičnosti potencialnih učinkovin za zdravljenje COVID-19

Bajželj, Matija (author), Anderluh, Marko (mentor)

Koronavirusno bolezen 2019 (COVID-19) povzroča koronavirus SARS-CoV-2, virus RNA z ovojnico. Zaradi hitrega širjenja nalezljive bolezni na vseh celinah je Svetovna zdravstvena organizacija COVID-19 razglasila za pandemijo. Bolezen lahko poteka v obliki lažje okužbe zgornjega dela dihalnega trakta ali v obliki hude virusne pljučnice z odpovedjo dihanja, lahko so prizadeti tudi preostali organski sistemi. V okviru magistrske naloge smo v prvem delu s pomočjo tuje literature pripravili sistematični pregled potencialnih zdravilnih učinkovin za COVID-19, ki so vključene v prenamembo učinkovin. V drugem delu naloge smo s programom Toxtree za vrednotenje toksičnosti in silico napovedali toksičnost potencialnih učinkovin za COVID-19, ki so v predkliničnih testiranjih. Opisali smo mehanizem delovanja učinkovin, rezultate prvih kliničnih študij in njihov varnostni profil. Na tej osnovi smo napovedali, kakšna je prihodnost teh učinkovin za prenamembo v klinični praksi. Učinkovine, ki smo jih vključili, so favipiravir, remdesivir, lopinavir/ritonavir, umifenovir, azitromicin, ruksolitinib in hidroksiklorokin. Rezultati kliničnih študij kažejo, da protivirusne učinkovine izboljšajo klinično stanje predvsem pri bolnikih z zmernim potekom bolezni. Pri bolnikih s težjim ali kritičnim potekom bolezni bi učinkovine z vplivom na imunski sistem oziroma blaženje citokinske nevihte lahko predstavljale večji potencial za zdravljenje. S Cramerjevimi razredi toksičnosti smo napovedali, da vse učinkovine uvrščamo v III. razred toksičnosti, zato predpostavljamo, da bodo za vse spojine potrebne še dodatne študije in vitro ter in vivo pred začetkom študij na ljudeh. Na osnovi strukture spojin smo pri 19 izmed 27 predvideli genotoksično in negenotoksično rakotvornost. Z orodjem SwissADME smo za 17 izmed 27 učinkovin določili potencialno zaviranje citokromov P450, kar bi lahko povečalo verjetnost za toksične učinke spojin ali interakcije z učinkovinami zaradi zmanjšane presnove, kar lahko povzroči povišanje plazemskih koncentracij teh spojin ali drugih učinkovin pri pacientih s polifarmacijo. Pri osmih spojinah nismo identificirali funkcionalnih skupin, ki bi bile lahko povezane s toksičnostjo, zato smo za te spojine napovedali največji potencial za nadaljnji razvoj v naslednjih kliničnih fazah.

• Language: Slovenian
• Keywords: Ključne besede: SARS-CoV-2, virusne učinkovine, učinkovine za blaženje citokinske nevihte, napoved toksičnosti in silico, program Toxtree
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-118225
• Publication date in RUL: 27.08.2020

Secondary language

• Language: English
• Title: Systematic review and toxicity prediction of potential COVID-19 drugs

Abstract

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because of the fast spreading of the disease World Health Organisation (WHO) declared COVID-19 pandemic at the beginning of 2020. The disease could have symptoms typical for an infection of upper respiratory tract or could proceed to severe virus pneumonia with respiratory failure. Other organ systems could also be affected. SARS-CoV-2 is an enveloped RNA virus. Binding to human angiotensin-converting enzyme is essential for the viral entry into host cells. In the first part of master thesis we prepared systematic review of potential COVID-19 drugs, that are potential candidates or have been designated for drug repurposing. In the second part we predicted in silico toxicity with a program Toxtree of compounds that are in preclinical studies for COVID-19. We described the mechanism of action, results of first clinical trials and safety profiles of potential COVID-19 drugs included in drug repurposing. According to that we predicted the potential of these drugs for the future use in clinical practice. Substances that are presented are favipiravir, remdesivir, lopinavir/ritonavir, umifenovir, azithromycin, ruxolitinib and hydroxychloroquine. The results of clinical trials show that antiviral drugs improve the clinical condition of patients with moderate course of disease. The drugs that affect immune system e. g. inhibit cytokine storm triggered by COVID-19 have the potential for the treatment of patients with severe or critical conditions. According to Cramer rules of toxicity all drugs were classified into high class (class III) of toxicity. Because of that additional in vitro and in vivo studies would be needed before these substances could be tested in humans. For 19 of 27 substances we identified the potential for causing genotoxic and nongenotoxic carcinogenicity. With the tool SwissADME we identified 17 of 27 compounds that could inhibit some of the cytochromes P450. These could lead to toxic effects and drug interactions because of the decreased metabolism rate and consequently higher plasma concentrations of either parent drugs ar other drugs in patients with polypharmacy. For 8 compounds we did not identify any functional groups that are related to toxicity. Therefore, we believe that these substances have the highest potential for the development in future clinical trials.

• Keywords: SARS-CoV-2, antiviral drugs, drugs to alleviate cytokine storm, in silico toxicity prediction, Toxtree