Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction, prevention of type-1 HRS associated with bacterial infections, and treatment of type-1 hepatorenal syndrome are the main indications. In these indications treatment with HSA is associated with improvement in survival. Albumin is a stable and very flexible molecule with a heart shape, 585 residues, and three domains of similar size, each one containing two sub-domains. Many of the physiological functions of HSA rely on its ability to bind an extremely wide range of endogenous and exogenous ligands, to increase their solubility in plasma, to transport them to specific tissues and organs, or to dispose of them when they are toxic. The chemical structure of albumin can be altered by some specific processes (oxidation, glycation) leading to rapid clearance and catabolism. An outstanding feature of HSA is its capacity to bind lipopolysaccharide and other bacterial products (lipoteichoic acid and peptidoglycan), reactive oxygen species, nitric oxide and other nitrogen reactive species, and prostaglandins. Binding to NO and prostaglandins are reversible, so they can be transferred to other molecules at different sites from their synthesis. Through these functions, HSA modulates the inflammatory reaction. Decompensated cirrhosis is a disease associated systemic inflammation, which plays an important role in the pathogenesis of organ or system dysfunction/failure. Although, the beneficial effects of HAS have been traditionally attributed to plasma volume expansion, they could also relate to its effects modulating systemic and organ inflammation.

NMR spectroscopy plays a major role in the determination of the structures and dynamics of proteins and other biological macromolecules. Chemical shifts are the most readily and accurately measurable NMR parameters, and they reflect with great specificity the conformations of native and nonnative states of proteins. We show, using 11 examples of proteins representative of the major structural classes and containing up to 123 residues, that it is possible to use chemical shifts as structural restraints in combination with a conventional molecular mechanics force field to determine the conformations of proteins at a resolution of 2 Å or better. This strategy should be widely applicable and, subject to further development, will enable quantitative structural analysis to be carried out to address a range of complex biological problems not accessible to current structural techniques.

Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease. Significance Parkinson’s disease is characterized by the accumulation of amyloid deposits in dopaminergic neurons, mainly composed of the protein α-synuclein. The disordered nature of α-synuclein and its complex aggregation reaction complicate the identification of molecules able to prevent or revert the formation of these inclusions and the subsequent neurodegeneration. By exploiting a recently developed high-throughput screening assay, we identified SynuClean-D, a small compound that inhibits α-synuclein aggregation, disrupts mature amyloid fibrils, prevents fibril propagation, and abolishes the degeneration of dopaminergic neurons in an animal model of Parkinson’s disease.