Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents
Abstract
:1. Introduction
2. Results
2.1. Preparation of Compound 1-Resistant HSV-1 Population
2.2. High-Throughput Sequencing of Resistant Clones
2.3. Molecular Modeling Study
2.3.1. Biological Target Analysis
2.3.2. Molecular Docking Results
Docking to the ATP Domain
Docking to Alternative Binding Sites
2.3.3. Molecular Dynamic Results
Molecular Dynamics of the 1–ATP-D Complex
Molecular Dynamics of the 1–CC Complex
Molecular Dynamics of 1–loop1 and 1–loop2 Complexes
3. Materials and Methods
3.1. Compounds
3.2. Viruses
3.3. Cells
3.4. Antiviral Tests
3.5. Cloning
3.6. Isolation of DNA from Herpesvirus-Infected Cells
3.7. High-Throughput Sequencing of Herpesvirus Genomes
3.8. Calculation Technique
3.8.1. Preparation of Protein and Ligand
3.8.2. Binding Site Analysis
3.8.3. Molecular Docking
3.8.4. Molecular Dynamics
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Virus | IC50 (µg/mL) | ||||||||
---|---|---|---|---|---|---|---|---|---|
Compound 1 | ACV | PCV | GCV | BVDU | IDU | CDV | Ara-A | FOS | |
HSV-1/L2 | 1.95 | 0.39 | 0.78 | 0.56 | 0.098 | 3.9 | 3.9 | 15.6 | 31.25 |
HSV-1/L2/R1 | 9.75 | 0.39 | 0.78 | 1.12 | 0.114 ± 0.08 | 3.9 | 3.9 | 15.6 | 31.25 |
Clone 1 | 20.0 | 0.39 | 0.78 | 0.78 | 0.122 | 3.9 | 3.9 | 15.6 | 31.25 |
Clone 2 | 20.0 | 0.39 | 0.78 | 0.78 | 0.106 ± 0.008 | 3.9 | 3.9 | 15.6 | 31.25 |
Clone 3 | 20.0 | 0.39 | 0.78 | 0.89 ± 0.11 | 0.098 | 3.9 | 3.9 | 15.6 | 31.25 |
Sample | Total Reads × 106 | Software Used for Mapping | |
---|---|---|---|
bowtie2 | bowtie2 (Local) | ||
Clone 1 | 5.75 | 15.33% | 15.54% |
Clone 2 | 5.11 | 23.39% | 23.69% |
Clone 3 | 5.36 | 23.80% | 24.13% |
Wild type | 6.41 | 20.41% | 20.67% |
Gene Array | Product | Position on Reference Genome | Mutation in Genome | Product |
---|---|---|---|---|
TRL3-UL3 | UL2 (uracil-DNA glycosylase) | 9940 | G→A | R19H |
UL13.5-UL15 | UL15 (large subunit of terminase) | 29,982 | C→T | T321I |
UL27.5-UL30 | UL30 (DNA polymerase) | 65,203 | C→T | E799D |
UL37-UL39.6 | UL37 (tegument protein) | 81,716 | C→T | R790H |
US5-US7 | US7 (glycoprotein I) | 140,281 | G→A | A165T |
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Krasnov, V.P.; Andronova, V.L.; Belyavsky, A.V.; Borisevich, S.S.; Galegov, G.A.; Kandarakov, O.F.; Gruzdev, D.A.; Vozdvizhenskaya, O.A.; Levit, G.L. Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents. Molecules 2023, 28, 7375. https://doi.org/10.3390/molecules28217375
Krasnov VP, Andronova VL, Belyavsky AV, Borisevich SS, Galegov GA, Kandarakov OF, Gruzdev DA, Vozdvizhenskaya OA, Levit GL. Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents. Molecules. 2023; 28(21):7375. https://doi.org/10.3390/molecules28217375
Chicago/Turabian StyleKrasnov, Victor P., Valeriya L. Andronova, Alexander V. Belyavsky, Sophia S. Borisevich, George A. Galegov, Oleg F. Kandarakov, Dmitry A. Gruzdev, Olga A. Vozdvizhenskaya, and Galina L. Levit. 2023. "Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents" Molecules 28, no. 21: 7375. https://doi.org/10.3390/molecules28217375
APA StyleKrasnov, V. P., Andronova, V. L., Belyavsky, A. V., Borisevich, S. S., Galegov, G. A., Kandarakov, O. F., Gruzdev, D. A., Vozdvizhenskaya, O. A., & Levit, G. L. (2023). Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents. Molecules, 28(21), 7375. https://doi.org/10.3390/molecules28217375