Probing the Topological Effects on Stability Enhancement and Therapeutic Performance of Protein Bioconjugates: Tadpole, Macrocycle versus Figure-of-Eight.

Chemical topology provides a unique dimension for making therapeutic protein bioconjugates with native structure and intact function, yet the effects of topology remain elusive. Herein, the design, synthesis, and characterization of therapeutic protein bioconjugates in three topologies (i.e.

Distinguishing Protein Chemical Topologies Using Supercharging Ion Mobility Spectrometry-Mass Spectrometry.

A technique combining ion mobility spectrometry-mass spectrometry (IMS-MS) and supercharging electrospray ionization (ESI) has been demonstrated to differentiate protein chemical topology effectively. Incorporating as many charges as possible into proteins via supercharging ESI allows the protein chains to be largely unfolded and stretched, revealing their hidden chemical topology. Different chemical topologies result in differing geometrical sizes of the unfolded proteins due to constraints in torsional rotations in cyclic domains.

Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma.

Background: The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin's lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling.

Methods: Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107.

Checkpoint therapeutic target database (CKTTD): the first comprehensive database for checkpoint targets and their modulators in cancer immunotherapy.

Background: Checkpoint targets play a key role in tumor-mediated immune escape and therefore are critical for cancer immunotherapy. Unfortunately, there is a lack of bioinformatics resource that compile all the checkpoint targets for translational research and drug discovery in immuno-oncology.

Methods: To this end, we developed checkpoint therapeutic target database (CKTTD), the first comprehensive database for immune checkpoint targets (proteins, miRNAs and LncRNAs) and their modulators.

Small-Molecule Antagonist Targeting Exportin-1 via Rational Structure-Based Discovery.

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829.