Design, synthesis and modeling of novel azole nucleoside analogs as potential therapeutics for RNA viruses.

摘要

Hantaviruses are tri-segmented negative stranded RNA viruses that are distributed worldwide and cause two acute febrile syndromes in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Although the nucleoside analog ribavirin (RBV) was shown to significantly reduce the mortality rate when administered early in the progression of the disease, it was ineffective for the treatment of HPS in the cardiopulmonary stage. Side effects including hemolytic anemia and teratogenic effects limit its clinical application. The objective of this investigation was to develop potential RNA antiviral agents based on azole-beta-ribosides that possess a wide variety of structural diversity.;We designed, modeled and synthesized a series of bio-isosteres, homologated analogs, and substituted derivatives possessing altered steric and hydrogen-bonding profiles. The antiviral activity of these compounds was evaluated against Hantaan virus (HTNV) and Andes virus (ANDV). The compound ETAR (1-beta-D-ribofuranosy1-3-ethynyl-[1,2,4]triazole) was identified as a potent anti-hantaviral agent from in vitro and in vivo studies. Its EC50 values for HTNV and ANDV were 10 muM and 4.4 muM respectively. Structure-activity relationships were studied using structural analogs of ETAR. The apparent mechanism of ETAR's antiviral activity is inhibition of inosine monophosphate dehydrogenase (IMPDH) and reduction of GTP levels. The docking studies of ETAR analogs with IMPDH and model reactions with ethanethiol favor the proposed mechanism that involves a nucleophilic attack by the IMPDH active site Cys331 on alkyne moiety.;Since the conversion of RBV to the monophosphate by human adenosine kinase (hADK) is the rate-limiting step in the activation of this broad-spectrum antiviral drug, we evaluated our compounds as substrates for hADK and their binding modes with hADK using an automated computational docking study. Results obtained from this study enabled us to explore the potential of azole-linked 1,2,4-triazole-beta-ribosides as hADK substrates. 1,2,3-Triazole-linked 1,2,4-triazole-beta-ribosides exhibited an increased hADK activity relative to other analogs, which can be attributed to the stacking interactions of triazole rings with the binding site Phe170. The results from this investigation provide a framework for the rational design of antivirals targeting other RNA viruses in addition to hantaviruses.