Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8 + T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLAlinked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.3D structure | small molecule | binding site A bacavir is a nucleoside analog that suppresses HIV replication. In approximately 8% of recipients, abacavir is associated with significant immune-mediated drug hypersensitivity, which is strongly associated with the presence of the HLA-B*57:01 allele (1, 2). Three complementary models for the mechanism of immune-mediated severe adverse drug reactions have traditionally been discussed (3, 4). The hapten (or prohapten) model states that drugs and their metabolites are too small to be immunogenic on their own, but rather act like haptens and modify certain self-proteins in the host that lead to immune recognition of the resulting hapten-self-peptide complexes as de novo antigens (5-7). The pharmacologic interaction with immune receptors (p-i) model states that drugs can induce the formation of HLA-drug complexes that can activate T-cell immune responses directly without requiring a specific peptide ligand (8). The danger model, which is in principle compatible with other models, states that danger signals other than the drug itself (e.g., chemical, physical, or viral stress) are required to overcome immune tolerance barriers that otherwise suppress drug hypersensitivity reactions (7).None of these existing models provides a convincing mechanism explaining how abacav...

Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. It is well established that neuronal nitric oxide synthase (nNOS)-derived NO exerts a negative control on the hippocampal neurogenesis. Using genetic and pharmacological methods, we investigated the roles of nNOS in depression induced by chronic mild stress (CMS) in mice. Hippocampal nNOS over-expression was first observed 4 days and remained elevated 21 and 56 days after exposure to CMS. The mice exposed to CMS exhibited behavioral changes typical of depression, and impaired neurogenesis in the hippocampus. The CMS-induced behavioral despair and hippocampal neurogenesis impairment were prevented and reversed in the null mutant mice lacking nNOS gene (nNOS)/)) and in the mice receiving nNOS inhibitor. Disrupting hippocampal neurogenesis blocked the antidepressant effect of nNOS inhibition. Moreover, nNOS)/) mice exhibited antidepressant-like properties. Our findings suggest that nNOS over-expression in the hippocampus is essential for chronic stress-induced depression and inhibiting nNOS signaling in brain may represent a novel approach for the treatment of depressive disorders.

In this work, a new set of amino acid descriptors, i.e., VHSE (principal components score Vectors of Hydrophobic, Steric, and Electronic properties), is derived from principal components analysis (PCA) on independent families of 18 hydrophobic properties, 17 steric properties, and 15 electronic properties, respectively, which are included in total 50 physicochemical variables of 20 coded amino acids. Using the stepwise multiple regression (SMR) method combined with partial least squares (PLS), the VHSE scales are then applied to QSAR studies of bitter-tasting dipeptides (BTD), angiotensin-converting enzyme (ACE) inhibitors, and bradykinin-potentiating pentapeptides (BPP). To validate the predictive power of resulting models, external validation are also performed. A comparison of the results to those obtained with z scores and other two-dimensional (2D) or three-dimensional(3D) descriptors shows that the VHSE scales are comparable for parameterizing the structural variability of the peptide series.

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