Background:Competitors of LEDGF binding to HIV-1 integrase could prevent targeted integration to chromatin. Results: LEDGF competitors like tBPQAs were also found to inhibit integrase enzyme activity by preventing proper integraseviral DNA assembly. Conclusion: tBPQAs are allosteric inhibitors of integrase with a dual mode of action. Significance: Interference with two distinct steps of integration through the same binding site represents a new antiviral paradigm.

The in vitro refolding of hen egg-white lysozyme is studied in the presence of various osmolytes. Proline is found to prevent aggregation during protein refolding. However, other osmolytes used in this study fail to exhibit a similar property. Experimental evidence suggests that proline inhibits protein aggregation by binding to folding intermediate~s! and trapping the folding intermediate~s! into enzymatically inactive, "aggregation-insensitive" state~s!. However, elimination of proline from the refolded protein mixture results in significant recovery of the bacteriolytic activity. At higher concentrations~Ͼ1.5 M!, proline is shown to form loose, higher-order molecular aggregate~s!. The supramolecular assembly of proline is found to possess an amphipathic character. Formation of higher-order aggregates is believed to be crucial for proline to function as a protein folding aid. In addition to its role in osmoregulation under water stress conditions, the results of this study hint at the possibility of proline behaving as a protein folding chaperone.

Background: Idelalisib is a PI3Kδ inhibitor used to treat hematological malignancies.Results: Idelalisib is selective, noncovalent, reversible, and ATP-competitive.Conclusion: The crystal structure helps explain the potency and selectivity of idelalisib. The biophysical and biochemical data clarify the details of the inhibitor's interactions with PI3Kδ.Significance: Its use in humans makes it important to understand how idelalisib inhibits PI3Kδ.

GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.

The three-dimensional structure of rice nonspecific lipid transfer protein (nsLTP2) has been solved for the first time. The structure of nsLTP2 was obtained using 813 distance constraints, 30 hydrogen bond constraints, and 19 dihedral angle constraints. Fifteen of the 50 random simulated annealing structures satisfied all of the constraints and possessed good nonbonded contacts. The novel three-dimensional fold of rice nsLTP2 contains a triangular hydrophobic cavity formed by three prominent helices. The four disulfide bonds required for stabilization of the nsLTP2 structure show a different pattern of cysteine pairing compared with nsLTP1. The C terminus of the protein is very flexible and forms a cap over the hydrophobic cavity. Molecular modeling studies suggested that the hydrophobic cavity could accommodate large molecules with rigid structures, such as sterols. The positively charged residues on the molecular surface of nsLTP2 are structurally similar to other plant defense proteins. Plant nonspecific lipid transfer proteins (nsLTPs)1 have been isolated from a number of plant species including wheat, rice, and barley (1). NsLTPs enhance the intermembrane exchange or transfer of lipid molecules in vitro (2). Biotic and abiotic stresses stimulate nsLTP gene expression (3-5). NsLTPs are known to be involved in the formation of a protective hydrophobic layer over the plant surfaces (5). Despite their ability to help plants to manage stress, the exact mechanism of transport is still unclear. NsLTPs are also involved in other biological activities such as flowering and transportation of cutin and suberin monomers (6). NsLTPs present in cereals play an important role in food chemistry. NsLTPs directly affect dough rheology and breadcrumb texture (6). Reports about the isolation of glycosylated and reduced nsLTP fragments from beer suggest that nsLTPs are involved in froth formation during the malting and brewing processes (7).NsLTPs are divided into two subfamilies, nsLTP1 (molecular mass ϳ9 kDa) and nsLTP2 (molecular mass ϳ7 kDa) (2). NsLTP1 is found primarily in aerial organs, whereas nsLTP2 is expressed in roots. Interestingly, both nsLTP1 and nsLTP2 are found in seeds. NsLTP1 is proposed to transport cutin monomers, whereas nsLTP2 is involved in the transport of the more rigid suberin monomers (6). Three-dimensional structures of nsLTP1 from various sources were determined by x-ray and NMR spectroscopic techniques (8). All nsLTP1s share a common structural fold stabilized by four disulfide bonds. The prominent four helices of nsLTP1 are packed against a flexible C-terminal arm formed by a series of turns. In contrast to many globular proteins, the hydrophobic side chains of nsLTP1 do not form a rigid hydrophobic core but instead form a hydrophobic cavity at the interior of the protein. Recently, we have purified nsLTP2 from rice. The amino acid sequence, disulfide bond pattern and stability have been determined (TrEMBL ID P83210) (9). Rice nsLTP2 contains 69 residues and has less than 30% sequence identity wi...