nw-1029 and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Neuropathic pain is among the most common and difficult-to-treat types of chronic pain and is associated with sodium channel malfunction. The sodium channel blocker ralfinamide has exhibited potent analgesic effects in several preclinical pain models and in patients with mixed neuropathic pain syndromes (Phase II trials), but it failed to ameliorate neuropathic low back pain in Phase III trials. It is unclear whether ralfinamide is effective against neuropathic pain induced by specified etiologies. In the present study, the antinociceptive effects of ralfinamide in neuropathic pain models induced by spared nerve injury and chemotherapy were compared in a gabapentin-controlled manner. The effects of ralfinamide on physiological pain were evaluated in mechanical withdrawal, hot plate, and acetic acid writhing tests. We also investigated the effects of ralfinamide on cardiovascular function and locomotor activity. Oral ralfinamide dose-dependently alleviated spared nerve injury-induced allodynia in rats and mice. Ralfinamide increased mechanical withdrawal thresholds in oxaliplatin-induced and paclitaxel-induced neuropathic pain. Ralfinamide did not affect physiological pain, locomotion, or cardiovascular function. Together, ralfinamide attenuated mechanical allodynia in all the neuropathic pain models tested, with subtle differences in efficacy. The effect of ralfinamide is comparable to that of gabapentin, but with no interference in basal mechanical sensitivity. The present study supports the effectiveness of selective sodium channel blockade as an analgesic strategy, as well as the development of compounds similar to ralfinamide.

Topics: Amines; Analgesics; Animals; Antineoplastic Agents; Blood Pressure; Cyclohexanecarboxylic Acids; Disease Models, Animal; Fluorobenzenes; Gabapentin; gamma-Aminobutyric Acid; Heart Rate; Locomotion; Male; Neuralgia; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Peripheral Nervous System; Rats; Rats, Sprague-Dawley