Artificial analogues of DNA mimic proteins functionalized
To specifically inhibit therapeutic target as HIV-1 integrase and human Topoisomerase 1
V. Parissi, MFP Bordeaux, P. Pourquier IRC Montpellier, I. Huc, LMU Munich
We have previously reported the generation of foldamers as artificial molecules that could bind and inhibit DNA binding proteins by mimicking nucleic acids (1). In order to develop new therapeutic agents we have functionalized these drugs leading to aromatic foldamers bearing phosphonate groups as synthetic mimics of the charge surface of B-DNA and competitive inhibitors of some therapeutically relevant DNA-binding enzymes: the human DNA Topoisomerase 1 (Top1) and the human HIV-1 integrase (HIV-1 IN). Proof of their resemblance to B-DNA was brought by the first crystal structure of one of these DNA-mimic foldamers in its polyanionic form. Some foldamers were found to have differential inhibitory effects on the two enzymes and, thus, have gained significant specificity toward these two important therapeutic targets. Further works under progress currently led us to produce new compounds showing specificity for several cellular factors that are involved in various diseases as cancers and viral infection. This work opens broad avenues for the development of new classes of derivatives that could inhibit the interaction of specific proteins with their DNA target thereby influencing the cellular pathways in which they are involved (2).
1. Ziach,K., Chollet,C., Parissi,V., Prabhakaran,P., Marchivie,M., Corvaglia,V., Bose,P.P., Laxmi-Reddy,K., Godde,F., Schmitter,J.-M., et al. (2018) Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA. Nat. Chem., 10, 511–518.
2. Corvaglia V, Carbajo D, Prabhakaran P, Ziach K, Mandal PK, Santos VD, Legeay C, Vogel R, Parissi V, Pourquier P, Huc I. Carboxylate-functionalized foldamer inhibitors of HIV-1 integrase and Topoisomerase 1: artificial analogues of DNA mimic proteins. Nucleic Acids Res. 2019 May 10. pii: gkz352. doi: 10.1093/nar/gkz352. [Epub ahead of print] PubMed PMID: 31073604.