Biological and mutational analyses of CXCR4-antagonist interactions and design of new antagonistic analogs.

The chemokine receptor CXCR4 has become an attractive therapeutic target for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. A wide variety of synthetic antagonists of CXCR4 have been developed and studied for a growing list of clinical applications. To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules.

HIV-1 gp120-CXCR4 recognition probed with synthetic nanomolar affinity D-peptides containing fragments of gp120 V3 loop.

The human immunodeficiency virus type 1 (HIV-1) recognizes one of its principal coreceptors, the CXC chemokine receptor 4 (CXCR4) on the host cell via the third variable loop (V3 loop) of HIV-1 envelope glycoprotein gp120 during the viral entry process. Here, we investigated the stereochemical mechanism of the molecular recognition of HIV-1 gp120 V3 loop with coreceptor CXCR4 by using peptide probes containing important fragments of the V3 loop. The tip and base/stem fragments of the V3 loop critical for V3 loop function were linked individually with the fragment derived from another CXCR4's chemokine ligand, vMIP-II to generate nanomolar affinity peptide probes of the interactions of CXCR4-V3 loop fragments.

Discoveries and developments of CXCR4-targeted HIV-1 entry inhibitors.

Unlabelled: The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and its expression correlates with more profound pathogenicity, rapid progression to acquired immunodeficiency syndrome (AIDS), and greater AIDS-related mortality. There is still no cure for AIDS and no method for preventing or eradicating HIV-1 infection. HIV-1 entry begins with the interaction of the viral envelope glycoprotein gp120 and the primary receptor CD4, and subsequently with the coreceptors, CCR5 or CXCR4, on the host cells.

High affinity CXCR4 inhibitors generated by linking low affinity peptides.

G-protein coupled receptors (GPCRs) are implicated in many diseases and attractive targets for drug discovery. Peptide fragments derived from protein ligands of GPCRs are commonly used as probes of GPCR function and as leads for drug development. However, these peptide fragments lack the structural integrity of their parent full-length protein ligands and often show low receptor affinity, which limits their research and therapeutic values.

The influence of unilateral contraction of hand muscles on the contralateral corticomuscular coherence during bimanual motor tasks.

The mechanisms behind how muscle contractions in one hand influence corticomuscular coherence in the opposite hand are still undetermined. Twenty-two subjects were recruited to finish bimanual and unimanual motor tasks. In the unimanual tasks, subjects performed precision grip using their right hand with visual feedback of exerted forces.