The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types
Abstract
:1. Introduction
2. Materials and Methods
2.1. Antiviral Compounds
2.2. Cultured Cells, SARS-CoV-2 Isolates and Reporter Viruses, and Fluorescence-Based and Multi-Readout Replication Assays
2.3. Assessment of Drug Interactions Using the Loewe Additivity Fixed Dose Method
3. Results
3.1. The Trimeric Artesunate Analog TF27 Inhibits SARS-CoV-2 Replication in Caco-2 Cells
3.2. Pretreatment Efficacy Demonstrates the Targeting of Host Cell Proteins
3.3. TF27 Inhibits SARS-CoV-2 Replication in Calu-3 Human Lung Cells and Is Active against Clinical Isolates including Delta and Omicron Variants
3.4. TF27 Exhibits Synergistic Interaction with GC376 but Antagonistic Interaction with EIDD-1931
4. Discussion
4.1. The Broad-Spectrum Antiviral Potential of Monomeric ART and Trimeric TF27 and Their Putative Relevance for the Development of Novel Anti-SARS-CoV-2 Treatment Strategies
4.2. Mechanistic Properties Based on the Host-Directed Mode of Antiviral Activity of Trimeric TF27, Parental ART, and Related Compounds
4.3. The Chances of Nominating a New Candidate for Studying Antiviral Properties in Clinical Settings and the Question of TF27-Induced Viral Drug Resistance
4.4. The Potential Benefit of TF27 as Part of a Combination Therapy to Achieve Improved Antiviral Efficacy by Exploiting Synergistic Drug Interactions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Trioxane Compounds | Type of Investigation | Antiviral Activity Analyzed | References |
---|---|---|---|
Artesunate and artemisinin | Review article | Various anti-herpesviral and non-herpesviral activities | [6] |
Artesunate | HHV-6A in cultured cells | Anti-HHV-6 activity | [15] |
Artesunate | EBV reporter system | Anti-EBV activity | [11] |
Artesunate and derivatives | Antiviral/mechanistic study | Broad-spectrum and NK-κB targeting | [10] |
Hybrid compounds | Chemistry, confocal imaging | Anti-HCMV and intracellular trafficking | [39] |
Trimers, dimers, and monomers | Antiviral/mechanistic study | TF27 unique, and strongest anti-HCMV drug | [19] |
TF27, analogs/dendrimers | Comparing bioactivities | TF27 strongest antiviral activity, and target ID | [18] |
TF27 | MDV/chicken model | Inhibits MDV replication and tumorigenesis | [12] |
TF27 | MCMV/mouse model | Intraperitoneal MCMV treatment efficacy | [26] |
TF27 | cCMV ex vivo model | Anti-cCMV high efficacy | [40] |
TF27 | MCMV/mouse model | Anti-MCMV oral prophylactic efficacy | [27] |
Autofluorescent BG95 | Confocal imaging a.o. | Anti-HCMV and mitochondrial targeting | [41] |
Linker model compounds | Target ID and verification | Mitochondrial/regulatory proteins as targets | [42] |
TF27 | Drug combination assessment | No true synergy TF27 + GCV | [43] |
TF27 compared to artesunate | Multi-readout system | Strong anti-SARS-CoV-2 activity | Present study |
HCMV/HFFs | SARS-CoV-2/Caco-2 | |||||||
---|---|---|---|---|---|---|---|---|
EC50 [µM] | CC50 [µM] | SI | Fold Increase Relative to ART | EC50 [µM] | CC50 [µM] | SI | Fold Increase Relative to ART | |
ART | 5.4 ± 0.6 | >10 | >2 | 1 | >40 | >100 | n.d. | 1 |
TF27 | 0.04 ± 0.01 | >10 | >250 | 113 | 0.46 ± 0.20 | >100 | >185 | >87 |
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Hahn, F.; Wangen, C.; Häge, S.; Herrmann, L.; Herrmann, A.; Tsogoeva, S.B.; Marschall, M. The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types. Pharmaceutics 2023, 15, 115. https://doi.org/10.3390/pharmaceutics15010115
Hahn F, Wangen C, Häge S, Herrmann L, Herrmann A, Tsogoeva SB, Marschall M. The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types. Pharmaceutics. 2023; 15(1):115. https://doi.org/10.3390/pharmaceutics15010115
Chicago/Turabian StyleHahn, Friedrich, Christina Wangen, Sigrun Häge, Lars Herrmann, Alexandra Herrmann, Svetlana B. Tsogoeva, and Manfred Marschall. 2023. "The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types" Pharmaceutics 15, no. 1: 115. https://doi.org/10.3390/pharmaceutics15010115
APA StyleHahn, F., Wangen, C., Häge, S., Herrmann, L., Herrmann, A., Tsogoeva, S. B., & Marschall, M. (2023). The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types. Pharmaceutics, 15(1), 115. https://doi.org/10.3390/pharmaceutics15010115