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1.  In silico Driven Redesign of a Clinically Relevant Antibody for the Treatment of GD2 Positive Tumors 
PLoS ONE  2013;8(5):e63359.
Ganglioside GD2 is a cell surface glycolipid that is highly expressed on cancer cells of neuroectodermal origin, including neuroblastoma, retinoblastoma, melanoma, sarcomas, brain tumors and small cell lung cancer. Monoclonal antibodies (MoAb) that target GD2 have shown clinical efficacy in the treatment of GD2 expressing tumors, and are expected to be the new standard of care for the treatment of pediatric neuroblastoma. In this study, the crystal structure of anti-GD2 murine MoAb 3F8 was solved to 1.65 Å resolution and used as a template for molecular docking simulations of its antigen, the penta-saccharide head group of GD2. Molecular docking revealed a binding motif composed of 12 key interacting amino acid side-chains, involving an extensive network of interactions involving main-chain and side-chain hydrogen bonding, two Pi – CH interactions, and an important charged interaction between Arg95 of the H3 loop with the penultimate sialic acid residue of GD2. Based on in silico scanning mutagenesis of the 12 interacting amino acids from the docked 3F8:GD2 model, a single point mutation (Heavy Chain: Gly54Ile) was engineered into a humanized 3F8 (hu3F8) MoAb and found to have a 6–9 fold enhancement in antibody-dependent cell-mediated cytotoxicity of neuroblastoma and melanoma cell lines. With enhanced tumor-killing properties, the re-engineered hu3F8 has the potential be a more effective antibody for the treatment of GD2-positive tumors.
PMCID: PMC3656052  PMID: 23696816
2.  Meditation as a Potential Therapy for Autism: A Review 
Autism Research and Treatment  2012;2012:835847.
Autism is a chronic neurodevelopmental disorder of unknown cause that affects approximately 1–3 percent of children and four times more boys than girls. Its prevalence is global and its social impact is devastating. In autism, the brain is unable to process sensory information normally. Instead, simple stimuli from the outside world are experienced as overwhelmingly intense and strain the emotional centers of the brain. A stress response to the incoming information is initiated that destabilizes cognitive networks and short-circuits adequate behavioral output. As a result, the child is unable to respond adequately to stimulation and initiate social behavior towards family, friends, and peers. In addition, these children typically face immune-digestive disorders that heighten social fears, anxieties, and internal conflicts. While it is critical to treat the physical symptoms, it is equally vital to offer an evidence-based holistic solution that harmonizes both their emotional and physical well-being as they move from childhood into adult life. Here, we summarize evidence from clinical studies and neuroscience research that suggests that an approach built on yogic principles and meditative tools is worth pursuing. Desired outcomes include relief of clinical symptoms of the disease, greater relaxation, and facilitated expression of feelings and skills, as well as improved family and social quality of life.
PMCID: PMC3420737  PMID: 22937260
3.  FKBP12 Binds to Acylated H-Ras and Promotes Depalmitoylation 
Molecular cell  2011;41(2):173-185.
A cycle of palmitoylation/depalmitoylation of H-Ras mediates bidirectional trafficking between the Golgi apparatus and the plasma membrane but nothing is known about how this cycle is regulated. We show that the prolyl isomerase (PI) FKBP12 binds to H-Ras in a palmitoylation-dependent fashion and promotes depalmitoylation. A variety of inhibitors of the PI activity of FKBP12, including FK506, rapamycin and cycloheximide, increase steady-state palmitoylation. FK506 inhibits retrograde trafficking of H-Ras from the plasma membrane to the Golgi in a proline 179-dependent fashion, augments early GTP-loading of Ras in response to growth factors, and promotes H-Ras dependent neurite outgrowth from PC12 cells. These data demonstrate that FKBP12 regulates H-Ras trafficking by promoting depalmitoylation through cis-trans isomerization of a peptidyl-prolyl bond in proximity to the palmitoylated cysteines.
PMCID: PMC3085165  PMID: 21255728
4.  Structural conversion of neurotoxic amyloid-β(1–42) oligomers to fibrils 
The Aβ42 peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low temperature and low salt can stabilize disc-shaped oligomers (pentamers) that are significantly more toxic to murine cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the β-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C-terminus is protected from solvent exchange and which have a turn conformation placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets whose individual β-strands polymerize in a parallel, in-register orientation and are staggered at an inter-monomer contact between Gln15 and Gly37.
PMCID: PMC2922021  PMID: 20383142
5.  Inhibitors of amyloid toxicity based on β-sheet packing of Aβ40 and Aβ42 
Biochemistry  2006;45(17):5503-5516.
Amyloid fibrils associated with Alzheimer’s disease and a wide range of other neurodegenerative diseases have a cross β-sheet structure where main chain hydrogen bonding occurs between β-strands in the direction of the fibril axis. The surface of the β-sheet has pronounced ridges and grooves when the individual β-strands have a parallel orientation and the amino acids are in-register with one another. Here we show that in Aβ amyloid fibrils, Met35 packs against Gly33 in the C-terminus of Aβ40 and against Gly37 in the C-terminus of Aβ42. These packing interactions suggest that the protofilament subunits are displaced relative to one another in the Aβ40 and Aβ42 fibril structures. We take advantage of this corrugated structure to design a new class of inhibitors that prevent fibril formation by placing alternating glycine and aromatic residues on one face of a β-strand. We show that peptide inhibitors based on a GxFxGxF framework disrupt sheet-to-sheet packing and inhibit the formation of mature Aβ fibrils as assayed by thioflavin T fluorescence, electron microscopy and solid-state NMR spectroscopy. The alternating large and small amino acids in the GxFxGxF sequence are complementary to the corresponding amino acids in the IxGxMxG motif found in the C-terminal sequence of Aβ40 and Aβ42. Importantly, the designed peptide inhibitors significantly reduce the toxicity induced by Aβ42 on cultured rat cortical neurons.
PMCID: PMC2593882  PMID: 16634632
amyloid fibrils; Alzheimer’s disease; solid-state NMR; GxxxG motif

Results 1-5 (5)