Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A
Artikel i vetenskaplig tidskrift, 2019

Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC 50 values vary from 0.077 μM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC 50 50–100 μM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy.

Enterovirus A

RAFIs

Tick-borne encephalitis virus

Perylene

Uracil-1-acetic acid

Författare

Alexey A. Chistov

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Alexey A. Orlov

Moscow State University

Russian Academy of Sciences

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Philipp P. Streshnev

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Nikita A. Slesarchuk

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Ilya O. Aparin

Skolkovo Institute of Science and Technology

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Brijesh Rathi

University of Delhi, Hans Raj College

Vladimir A. Brylev

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Biotech Industry Ltd

Sergey V. Kutyakov

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Irina V. Mikhura

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Alexey V. Ustinov

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Gunnar Westman

Chalmers, Kemi och kemiteknik, Kemi och biokemi

Vladimir A. Palyulin

Moscow State University

Nidhi Jain

Indian Institute of Technology Delhi

Dmitry I. Osolodkin

Moscow State University

Russian Academy of Sciences

Sechenov First Moscow State Medical University

Liubov I. Kozlovskaya

Russian Academy of Sciences

Sechenov First Moscow State Medical University

Vladimir A. Korshun

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

European Journal of Medicinal Chemistry

0223-5234 (ISSN)

Vol. 171 93-103

Ämneskategorier

Biokemi och molekylärbiologi

Läkemedelskemi

Organisk kemi

DOI

10.1016/j.ejmech.2019.03.029

Mer information

Senast uppdaterat

2019-04-29