Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine DOI Creative Commons

Leon Schrell,

Hannah L Fuchs,

Antje Dickmanns

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 6, 2024

ABSTRACT RNA viruses present a constant threat to human health, often with limited options for vaccination or therapy. Notable examples include influenza and coronaviruses, which have pandemic potential. Filo- henipaviruses cause more outbreaks, but high case fatality rates. All rely on the activity of virus-encoded RNA-dependent polymerase (RdRp). An antiviral nucleoside analogue, 4′-Fluorouridine (4′-FlU), targets RdRp diminishes replication several viruses, including A virus SARS-CoV-2, through incorporation into nascent viral delayed chain termination. However, effective concentration 4′-FlU varied among different raising need fortify its efficacy. Here we show that inhibitors dihydroorotate dehydrogenase (DHODH), an enzyme essential pyrimidine biosynthesis, can synergistically enhance effect against henipaviruses, Ebola virus. Even 4′-FlU-resistant mutant was re-sensitized towards by DHODH inhibition. The addition uridine rescued replication, strongly suggesting depletion as mechanism this synergy. also highly SARS-CoV-2 in hamster model COVID. We propose impairment endogenous synthesis inhibition enhances RNAs. This strategy may be broadly applicable efficacy analogues Graphical Abstract HIGHLIGHTS Strong synergy Activity combination previously resistant Broadly active diverse set Successful pathogenic Nipah

Язык: Английский

Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine DOI Creative Commons

Leon Schrell,

Hannah L Fuchs,

Antje Dickmanns

и другие.

Antiviral Research, Год журнала: 2024, Номер 233, С. 106046 - 106046

Опубликована: Дек. 3, 2024

RNA viruses present a constant threat to human health, often with limited options for vaccination or therapy. Notable examples include influenza and coronaviruses, which have pandemic potential. Filo- henipaviruses cause more outbreaks, but high case fatality rates. All rely on the activity of virus-encoded RNA-dependent polymerase (RdRp). An antiviral nucleoside analogue, 4'-Fluorouridine (4'-FlU), targets RdRp diminishes replication several viruses, including A virus SARS-CoV-2, through incorporation into nascent viral delayed chain termination. However, effective concentration 4'-FlU varied among different raising need fortify its efficacy. Here we show that inhibitors dihydroorotate dehydrogenase (DHODH), an enzyme essential pyrimidine biosynthesis, can synergistically enhance effect against henipaviruses, Ebola virus. Even 4'-FlU-resistant mutant was re-sensitized towards by DHODH inhibition. The addition uridine rescued replication, strongly suggesting depletion as mechanism this synergy. also highly SARS-CoV-2 in hamster model COVID. We propose impairment endogenous synthesis inhibition enhances RNAs. This strategy may be broadly applicable efficacy analogues

Язык: Английский

Процитировано

2
Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine DOI Creative Commons

Leon Schrell,

Hannah L Fuchs,

Antje Dickmanns

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 6, 2024

ABSTRACT RNA viruses present a constant threat to human health, often with limited options for vaccination or therapy. Notable examples include influenza and coronaviruses, which have pandemic potential. Filo- henipaviruses cause more outbreaks, but high case fatality rates. All rely on the activity of virus-encoded RNA-dependent polymerase (RdRp). An antiviral nucleoside analogue, 4′-Fluorouridine (4′-FlU), targets RdRp diminishes replication several viruses, including A virus SARS-CoV-2, through incorporation into nascent viral delayed chain termination. However, effective concentration 4′-FlU varied among different raising need fortify its efficacy. Here we show that inhibitors dihydroorotate dehydrogenase (DHODH), an enzyme essential pyrimidine biosynthesis, can synergistically enhance effect against henipaviruses, Ebola virus. Even 4′-FlU-resistant mutant was re-sensitized towards by DHODH inhibition. The addition uridine rescued replication, strongly suggesting depletion as mechanism this synergy. also highly SARS-CoV-2 in hamster model COVID. We propose impairment endogenous synthesis inhibition enhances RNAs. This strategy may be broadly applicable efficacy analogues Graphical Abstract HIGHLIGHTS Strong synergy Activity combination previously resistant Broadly active diverse set Successful pathogenic Nipah

Язык: Английский

Процитировано

0