In vitro and in vivo studies of a potent capsid-binding inhibitor of enterovirus 71.

OBJECTIVES: Enterovirus 71 (EV-A71) is an important pathogen that can cause severe neurological symptoms and even death. Our aim was to identify potent anti-EV-A71 compounds and study their underlying mechanisms and in vivo activity. METHODS: We identified a potent imidazolidinone derivative (abbreviated to PR66) as an inhibitor of EV-A71 infection from the screening of compounds and subsequent structure-based modification. Time-course treatments and resistant virus selection of PR66 were employed to study the mode of mechanism of PR66. In vivo activity of PR66 was tested in the ICR strain of new-born mice challenged with EV-A71/4643/MP4. RESULTS: PR66 could impede the uncoating process during viral infection via interaction with capsid protein VP1, as shown by a resistant virus selection assay. Using site-directed mutagenesis, we confirmed that a change from valine to phenylalanine in the 179th amino acid residue of the cDNA-derived resistant virus resulted in resistance to PR66. PR66 increased the virion stability of WT viruses, but not the PR66-resistant mutant, in a particle stability thermal release assay. We further showed that PR66 had excellent anti-EV-A71 activity in an in vivo mouse model of disease, with a dose-dependent increase in survival rate and in protection against virus-induced hind-limb paralysis following oral or intraperitoneal administration. This was associated with reductions of viral titres in brain and muscle tissues. CONCLUSIONS: We demonstrated here for the first time that an imidazolidinone derivative (PR66) could protect against EV-A71-induced neurological symptoms in vivo by suppressing EV-A71 replication. This involved binding to and restricting viral uncoating.

Clinical effectiveness of acupuncture for carpal tunnel syndrome.

Acupuncture and electroacupuncture treatments of symptomatic carpal tunnel syndrome (CTS) may improve symptoms and aid nerve repair as well as improve sensory and motor functions. However, limited evidence is available regarding the effects of these treatments based on comprehensive evaluation methods. This research completed the treatment and evaluation of 26 patients with confirmed CTS. Participants were divided into two treatment groups based on a modified neurophysiological grading scale. Of the total number of participants, 15 received acupuncture and 11 received electroacupuncture on both upper limbs. Acupoints were PC-7 (Daling) and PC-6 (Neiguan) along the pericardial meridian compatible with the median nerve tract. The treatment program consisted of 24 sessions of 15 min duration over 6 weeks. After electroacupuncture treatments, symptom severity was evaluated using the short clinical questionnaire by Lo and Chiang, which indicated improvements in the respective symptom severity score. After the acupuncture treatment, grip strength in the major symptomatic side in CTS patients could be significantly increased. Electrophysiology evaluation likewise indicated a significant increase in the distal median motor amplitude of the palm-wrist segment. In addition, Tinel's sign significantly decreased in the major symptomatic side. Our findings indicated that electroacupuncture could improve symptomatology, while acupuncture could exert positive therapeutic effects for CTS patients, as evidenced by improved symptomatology, grip strength, electrophysiological function, and physical provocation sign.