Probing GFP Chromophore Analogs as Anti-HIV Agents Targeting LTR-III G-Quadruplex

• Published in: Biomolecules (Basel, Switzerland) Vol. 11; no. 10; p. 1409
• Main Authors: Ryazantsev, Dmitriy Y, Myshkin, Mikhail Yu, Alferova, Vera A, Tsvetkov, Vladimir B, Shustova, Elena Y, Kamzeeva, Polina N, Kovalets, Polina V, Zaitseva, Elvira R, Baleeva, Nadezhda S, Zatsepin, Timofei S, Shenkarev, Zakhar O, Baranov, Mikhail S, Kozlovskaya, Liubov I, Aralov, Andrey V
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.09.2021; MDPI
• Subjects: Anti-HIV Agents - chemistry; antiviral activity; Antiviral agents; Binding sites; Chromophores; Congeners; Cytotoxicity; Drug development; Experiments; Fluorescence resonance energy transfer; FRET-melting; G-quadruplex; G-Quadruplexes; Gene expression; Green fluorescent protein; green fluorescent protein (GFP) chromophore; Green Fluorescent Proteins - chemistry; Green Fluorescent Proteins - pharmacology; High-throughput screening; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Long Terminal Repeat - drug effects; HIV Long Terminal Repeat - genetics; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - pathogenicity; Human immunodeficiency virus; Humans; Ligands; Long terminal repeat; Magnetic Resonance Spectroscopy; Microscopy; Models, Molecular; Molecular modelling; NMR; Nuclear magnetic resonance; Simulation; Solvents; Structure-Activity Relationship; Structure-activity relationships; Therapeutic targets; Viruses; St Louis Missouri; United States > US; Russia; FRET-melting; antiviral activity; cytotoxicity; green fluorescent protein (GFP) chromophore; G-quadruplex
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11101409

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.