ABSTRACT
Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2s Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) - a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A silencing of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.
ABSTRACT
@#Anaplastic lymphoma kinase (ALK) inhibitors are regarded as effective drugs for the treatment of ALK-positive NSCLC. However,the emergence of drug resistance has limited its further clinical application. This article briefly introduces the resistance mechanism of ALK inhibitors including acquired secondary mutations,gene amplification,bypass signaling pathway activation and reviews the recent advances on the reversal strategies such as drug combination,developing novel PROTACs to overcome drug resistance,so as to provide some reference for the development of ALK inhibitors.