Probing GFP Chromophore Analogs as Anti-HIV Agents Targeting LTR-III G-Quadruplex
| Autor: | Polina V. Kovalets, Dmitriy Yu. Ryazantsev, Mikhail Yu. Myshkin, Mikhail S. Baranov, Andrey V. Aralov, Timofei S. Zatsepin, Nadezhda S. Baleeva, Zakhar O. Shenkarev, Elvira R. Zaitseva, Elena Y. Shustova, Vladimir B. Tsvetkov, Liubov I. Kozlovskaya, Vera A. Alferova, Polina N. Kamzeeva |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Molecular model medicine.drug_class Anti-HIV Agents Green Fluorescent Proteins HIV Infections G-quadruplex Biochemistry Microbiology Article Green fluorescent protein chemistry.chemical_compound Structure-Activity Relationship medicine Humans Molecular Biology HIV Long Terminal Repeat Chemistry green fluorescent protein (GFP) chromophore Long terminal repeat QR1-502 G-Quadruplexes Förster resonance energy transfer Targeted drug delivery HIV-1 antiviral activity cytotoxicity Antiviral drug FRET-melting DNA |
| Zdroj: | Biomolecules, Vol 11, Iss 1409, p 1409 (2021) Biomolecules Volume 11 Issue 10 |
| Popis: | Green fluorescent protein (GFP) chromophore and its congeners draw significant attention mostly for bioimaging purposes. In this work we probed these compounds as antiviral agents. We have chosen LTR-III DNA G4, the major G-quadruplex (G4) present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), as the target for primary screening and designing antiviral drug candidates. The stabilization of this G4 was previously shown to suppress viral gene expression and replication. FRET-based high-throughput screening (HTS) of 449 GFP chromophore-like compounds revealed a number of hits, sharing some general structural features. Structure-activity relationships (SAR) for the most effective stabilizers allowed us to establish structural fragments, important for G4 binding. Synthetic compounds, developed on the basis of SAR analysis, exhibited high LTR-III G4 stabilization level. NMR spectroscopy and molecular modeling revealed the possible formation of LTR-III G4-ligand complex with one of the lead selective derivative ZS260.1 positioned within the cavity, thus supporting the LTR-III G4 attractiveness for drug targeting. Selected compounds showed moderate activity against HIV-I (EC50 1.78–7.7 μM) in vitro, but the activity was accompanied by pronounced cytotoxicity. |
| Databáze: | OpenAIRE |
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