The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

Coenzyme Q₁₀ (CoQ₁₀) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ₁₀ participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ₁₀ deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ₁₀ biosynthesis. These defects lead to reduced CoQ₁₀ levels and impaired mitochondrial functions. Clinically, primary CoQ₁₀ deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ₁₀, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ₁₀ biology, biosynthesis, and the clinical spectrum of primary CoQ₁₀ deficiencies, and we discuss emerging mechanisms linking CoQ₁₀ depletion to mitochondrial dysfunctions and human diseases.