CL-197

Human enterovirus (EV) pathogens cause various contagious diseases such as hand, foot, and mouth disease, encephalitis, myocarditis, acute flaccid myelitis, pneumonia, and bronchiolitis, which have become serious health threats. However, except for the EV71 vaccine on the market, there are no effective strategies to prevent and treat other EV pathogen infections. Therefore, broad-spectrum anti-EV drugs are urgently needed. In this study, we demonstrated that FNC, a small nucleoside analog inhibitor that has been demonstrated to be a potent inhibitor of HIV and entered into a clinical phase II trial in China, potently inhibits the viral replication of a multitude of EVs at the nanomolar level. Further investigation revealed that FNC inhibits positive- and negative-strand RNA synthesis of EVs by interacting and interfering with the activity of EV71 viral RNA-dependent RNA polymerase (3D pol ). Our findings demonstrate for the first time that FNC is an effective broad-spectrum inhibitor for human EV pathogens.

2'-Deoxy-2'-β-fluoroadenosines bearing 4'-azido or 4'-ethynyl groups designed for the treatment of HIV-1 infection have been synthesized.All these compounds possess nanomolar anti-HIV-1 activity, with the 4'-ethynyl-2-fluoroadenosine analog 1c (CL-197) being the most potent compound with low cytotoxicity (EC₅₀ = 0.9 nM, CC₅₀ > 100μM).It also shows potent inhibitory activities on drug resistant and clin. HIV-1 strains.Oral administration of 1c to Beagle dogs resulted in high levels of its bioactive form 1c-TP in peripheral blood mononuclear cells, the HIV-1 target cells, where the resulting triphosphate exhibited a long-term intracellular retention and could prevent HIV-1 infection for an extended time.1C displayed low in vivo toxicity and favorable pharmacokinetics profiles in Sprague-Dawley rats.The preclin. data support further development of 1c as a highly potent and orally bioavailable clin. candidate to treat HIV-1 infection.Currently, CL-197 is in clin. trials in China (registration number: CXHL2200529).