Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses DOI
Malaika D. Argade, Jazmin Galván Achi,

Ryan Bott

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Ebola and Marburg (EBOV MARV) filoviral infections lead to fatal hemorrhagic fevers have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating diseases. To address this unmet medical need, we conducted a systematic structural optimization of an early compound, N-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (1), borne from our previously reported hit-to-lead effort. This secondary round structure–activity relationship (SAR) involved design synthesis several deconstructed reconstructed analogs compound 1, which were then tested against pseudotyped EBOV MARV. The antiviral activities most promising leads further validated infectious assays. optimized exhibited desirable activity different ebolaviruses reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates vivo efficacy studies as part ongoing drug discovery campaign

Language: Английский

Minor electrostatic changes robustly increase VP40 membrane binding, assembly, and budding of Ebola virus matrix protein derived virus-like particles DOI Creative Commons

Balindile B. Motsa,

Tej Sharma, Michael D. Cioffi

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(5), P. 107213 - 107213

Published: March 24, 2024

Ebola virus (EBOV) is a filamentous negative-sense RNA which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it important to get detailed understanding the lifecycle illuminate new drug targets. EBOV encodes matrix protein, VP40, regulates assembly budding virions from inner leaflet host cell plasma membrane (PM). In this work we determine effects VP40 mutations altering electrostatics on PM interactions subsequent budding. that modify surface affect viral by binding capabilities. Mutations increase net positive charge one (e.g., Gly Arg Asp Ala) affinity phosphatidylserine (PS) PI(4,5)P2 in PM. This increased enhances association efficiency leading more effective formation virus-like particles (VLPs). contrast, decrease Asp) lead because decreased with anionic Taken together our results highlight sensitivity slight electrostatic changes Understanding single amino acid substitutions will be useful explaining infectivity virulence different strains, variants occur nature, long-term discovery endeavors aimed at

Language: Английский

Citations

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

Leon Schrell,

Hannah L Fuchs,

Antje Dickmanns

et al.

Antiviral Research, Journal Year: 2024, Volume and Issue: 233, P. 106046 - 106046

Published: Dec. 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

Language: Английский

Citations

3
Ebola disease: bridging scientific discoveries and clinical application DOI
Amanda Rojek,

Joshua Fieggen,

Paska Apiyo

et al.

The Lancet Infectious Diseases, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

Citations

1
Discovery of Nanosota-EB1 and -EB2 as Novel Nanobody Inhibitors Against Ebola Virus Infection DOI Creative Commons
Fan Bu, Gang Ye,

Kimberly M. Morsheimer

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(12), P. e1012817 - e1012817

Published: Dec. 23, 2024

The Ebola filovirus (EBOV) poses a serious threat to global health and national security. Nanobodies, type of single-domain antibody, have demonstrated promising therapeutic potential. We identified two anti-EBOV nanobodies, Nanosota-EB1 Nanosota-EB2, which specifically target the EBOV glycoprotein (GP). Cryo-EM biochemical data revealed that binds glycan cap GP1, preventing its protease cleavage, while Nanosota-EB2 critical membrane-fusion elements in GP2, stabilizing it pre-fusion state. is potent neutralizer infection vitro offers excellent protection mouse model challenge, provides moderate neutralization protection. are first nanobodies shown inhibit authentic EBOV. Combined with our newly developed structure-guided evolution approach, they lay foundation for nanobody-based therapies against other viruses within ebolavirus genus.

Language: Английский

Citations

1
Minor changes in electrostatics robustly increase VP40 membrane binding, assembly, and budding of Ebola virus matrix protein derived virus-like particles DOI Creative Commons

Balindile B. Motsa,

Tej Sharma, Prem P. Chapagain

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 31, 2024

Abstract Ebola virus (EBOV) is a filamentous negative-sense RNA which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it important to get detailed understanding the lifecycle illuminate new drug targets. EBOV encodes matrix protein, VP40, regulates assembly budding virions from inner leaflet host cell plasma membrane (PM). In this work we determine effects VP40 mutations altering electrostatics on PM interactions subsequent budding. that modify surface affect viral by binding capabilities. Mutations increase net positive charge one (e.g., Gly Arg Asp Ala) affinity phosphatidylserine (PS) PI(4,5)P 2 in PM. This increased enhances association efficiency leading more effective formation virus-like particles (VLPs). contrast, decrease Asp) lead because decreased with anionic Taken together our results highlight sensitivity slight electrostatic changes Understanding single amino acid substitutions will be useful explaining infectivity virulence different strains, variants occur nature, long-term discovery endeavors aimed at

Language: Английский

Citations

0
Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine DOI Creative Commons

Leon Schrell,

Hannah L Fuchs,

Antje Dickmanns

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 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

Language: Английский

Citations

0
Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses DOI
Malaika D. Argade, Jazmin Galván Achi,

Ryan Bott

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Ebola and Marburg (EBOV MARV) filoviral infections lead to fatal hemorrhagic fevers have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating diseases. To address this unmet medical need, we conducted a systematic structural optimization of an early compound, N-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (1), borne from our previously reported hit-to-lead effort. This secondary round structure–activity relationship (SAR) involved design synthesis several deconstructed reconstructed analogs compound 1, which were then tested against pseudotyped EBOV MARV. The antiviral activities most promising leads further validated infectious assays. optimized exhibited desirable activity different ebolaviruses reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates vivo efficacy studies as part ongoing drug discovery campaign

Language: Английский

Citations

0