96 research outputs found
Small-molecule CaVĪ±1ā CaVĪ² antagonist suppresses neuronal voltage-gated calcium-channel trafficking
Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming Ī±1 subunit (CaVĪ±1) that is engaged in protein-protein interactions with auxiliary Ī±2/Ī“ and Ī² subunits. The high-affinity CaV2.2Ī±1ā
CaVĪ²3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2Ī±1ā
CaVĪ²3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the Ī±-helix of CaV2.2Ī±1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVĪ²3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule Ī±-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking
Small molecules inhibit ex vivo tumor growth in bone
Bone is a common site of metastasis for breast, prostate, lung, kidney and other cancers. Bone metastases are incurable, and substantially reduce patient quality of life. To date, there exists no small-molecule therapeutic agent that can reduce tumor burden in bone. This is partly attributed to the lack of suitable in vitro assays that are good models of tumor growth in bone. Here, we take advantage of a novel ex vivo model of bone colonization to report a series of pyrrolopyrazolone small molecules that inhibit cancer cell invasion and ex vivo tumor growth in bone at single-digit micromolar concentration. We find that the compounds modulated the expression levels of genes associated with bone-forming osteoblasts, bone-destroying osteoclasts, cancer cell viability and metastasis. Our compounds provide chemical tools to uncover novel targets and pathways associated with bone metastasis, as well as for the development of compounds to prevent and reverse bone tumor growth in vivo
Kinetics of Surface-Induced Dissociation of N(CH3)4+ and N(CD3)4+ Using Silicon Nanoparticle Assisted Laser Desorption/Ionization and Laser Desorption/Ionization
Comparative studies of 193-nm photodissociation and TOF-TOFMS analysis of bradykinin analogues: The effects of charge site(s) and fragmentation timescales
Direct dynamics study of N-protonated diglycine surface-induced dissociation. Influence of collision energy
Role of E166 in the Imine to Enamine Tautomerization of the Clinical Ī²-Lactamase Inhibitor Sulbactam
Neutralization of methyl cation via chemical reactions in low-energy ion-surface collisions with fluorocarbon and hydrocarbon self-assembled monolayer films
Surface Deposition Resulting from Collisions between Diglycine and Chemically Modified Alkylthiolate Self-Assembled Monolayer Surfaces
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