G-quadruplexes in microbial genomes: stabilization of LTR-III in HIV-1 as potential therapeutic targets Zainab Albader 1 and Ramon Vilar 1 1 Imperial College London, UK b- CID: 01646940; Email: z.albader19@imperial.ac.uk. c-Supervisor; Email: r.vilar@imperial.ac.uk Guanine quadruplexes which is rich in guanine nitrogenous bases is a tetra-stranded structure that is fold due to the ability of guanines to display hydrogen bonds. These G-quadruplexes is further stabilized by electrostatic force between a mono cation (Na + or K + ) and the oxygen atoms of the guanine bases. Investigation of G-quadruplexes in microbial genomes are gaining increasing attention, especially with the challenges associated to antimicrobial resistance. Stabilization of G-quadruplexes present in gene promoter regions using small molecules can be a potential therapeutic target in microbial genomes. In this project, we aim to stabilize G-quadruplex structures in the gene promoter regions; thus, studying the effect of G-quadruplex formation in the unusual hybrid G-quadruplex structure LTR-III promoter in the HIV-1 virus. To stabilize LTR-III in HIV-1, we synthesized metal salphen complexes with different building blocks via click chemistry. Biophysical studies were conducted to evaluate the binding towards LTRIII and other G-quadruplexes. The metal salphen complexes are selectively bind to LTRIII with higher delta T values comparing to other G-quadruplexes and duplex DNA. CD spectra and FID assays were conducted for further understanding besides to docking to identify the bindings’ sites. References 1. Met. Ions Life Sci. 2018, 18, 325–349. 2. Comprehensive Supramolecular Chemistry II, 2017, 39–70.
3. Chem. Eur. J. 2019,25,417 –430. 4. Biol. Chem. 2001, 382, 621–628. 5. Nucleic Acids Res. 2006, 34, 5402–5415.
6. Drug Discovery. 2011,10, 261–275. 7. Trends Cell Biol. 2009, 19, 414–422. 8. Nucleic Acids Res. 2015, 43, 8627–8637. 9. Rev. Mol. Cell Bio. 2017, 18, 279–284.Nat. Rev. Chem. 2017, 1, 1–10. 10. Bioorg. Med. Chem. Lett. 2014, 24, 2602–2612. 11. Antimicrob. Chemother. 2014, 69, 3248–3258.Trends Microbiol. 2019, 27, 148–163. 12. Nucleic Acids Res. 2018; 7, 3270–3283. 13. Am. Chem. Soc. 2018, 140, 13654−13662. Med. Chem. 2013, 56, 6521−6530.
P01
© The Author(s), 2023
Made with FlippingBook Learn more on our blog