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1.  Amphipathic properties of HIV-1 gp41 fusion inhibitors 
Current topics in medicinal chemistry  2011;11(24):3022-3032.
Small molecule inhibition of HIV fusion has been an elusive goal, despite years of effort by both pharmaceutical and academic laboratories. In this review, we will discuss the amphipathic properties of both peptide and small molecule inhibitors of gp41-mediated fusion. Many of the peptides and small molecules that have been developed target a large hydrophobic pocket situated within the grooves of the coiled coil, a potential hotspot for inhibiting the trimer of hairpin formation that accompanies fusion. Peptide studies reveal molecular properties required for effective inhibition, including elongated structure and lipophilic or amphiphilic nature. The characteristics of peptides that bind in this pocket provide features that should be considered in small molecule development. Additionally, a novel site for small molecule inhibition of fusion has recently been suggested, involving residues of the loop and fusion peptide. We will review the small molecule structures that have been developed, evidence pointing to their mechanism of action and strategies towards improving their affinity. The data points to the need for a strongly amphiphilic character of the inhibitors, possibly as a means to mediate the membrane - protein interaction that occurs in gp41 in addition to the protein – protein interaction that accompanies the fusion-activating conformational transition.
PMCID: PMC3219813  PMID: 22044226
2.  Development of indole compounds as small molecule fusion inhibitors targeting HIV-1 glycoprotein-41 
Journal of medicinal chemistry  2011;54(20):7220-7231.
Non-peptide inhibition of fusion remains an important goal in anti-HIV research, due to its potential for low cost prophylaxis or prevention of cell–cell transmission of the virus. We report here on a series of indole compounds that have been identified as fusion inhibitors of gp41 through a structure-based drug design approach. Experimental binding affinities of the compounds for the hydrophobic pocket were strongly correlated to fusion inhibitory data (R2 = 0.91), and corresponding inhibition of viral replication confirmed the hydrophobic pocket as a valid target for low molecular weight fusion inhibitors. The most active compound bound to the hydrophobic pocket and inhibited cell-cell fusion and viral replication at sub-µM levels. A common binding mode for the inhibitors in this series was established by carrying out docking studies using structures of gp41 in the Protein Data Bank. The molecules were flexible enough to conform to the contours of the pocket, and the most active compound was able to adopt a structure mimicking the hydrophobic contacts of the D-peptide PIE7. The results enhance our understanding of indole compounds as inhibitors of gp41.
PMCID: PMC3234170  PMID: 21928824
gp41; small molecule; fusion inhibitor; docking; indole
3.  Paramagnetic relaxation assisted docking of a small indole compound in the HIV-1 gp41 hydrophobic pocket 
ACS chemical biology  2011;6(3):267-274.
The hydrophobic pocket contained within the gp41 coiled coil is an important target for small molecules designed to inhibit HIV-1 fusion. While various screening experiments have identified molecules purported to bind in this pocket, few have confirmed details of the interaction, instead relying on computational docking to predict the binding mode. This is made more challenging by the fact that residues lining the hydrophobic pocket are highly flexible, as is typical for a protein - protein interaction site, limiting the predictive power of computational tools. In this study, we report on an NMR method to define the binding mode of 1-5i, a compound in a series of newly developed indole inhibitors. We show that paramagnetic relaxation enhancement of ligand protons due to an MTSL group positioned close to the binding pocket could be applied quantitatively to distinguish between more than 30 different computational poses, selecting a single pose that agreed with the NMR data. In this pose, important hydrophobic and polar contacts occur with pocket lysine, tryptophan and glutamine residues, including putative hydrogen bonds between the ligand carboxylate and the lysine ε-amino group. A study of the ligand orientation suggests directions for optimization.
PMCID: PMC3060958  PMID: 21155611
4.  Design, Synthesis and Evaluation of Indole Compounds as Novel Inhibitors targeting Gp41 
A series of indole ring containing compounds were designed based on the structure of the gp41 complex in the region of the hydrophobic pocket. These compounds were synthesized using a Suzuki Coupling reaction, and evaluated using a fluorescence binding assay and cell-cell fusion assay. The observed inhibition constant of compound 7 was 2.1µM, and the IC50 for cell-cell fusion inhibition was 1.1µM. Assay data indicated that 7 is a promising lead compound for optimization into an effective low molecular weight fusion inhibitor.
PMCID: PMC2833348  PMID: 20153190
HIV; gp41; small molecule inhibitor; lead optimization; indole rings
5.  NMR second site screening for structure determination of ligands bound in the hydrophobic pocket of HIV-1 gp41 
The development of non-peptide fusion inhibitors through rational drug design has been hampered by the limited accessibility of the gp41 coiled coil target, which is highly hydrophobic, and the absence of structural data defining details of small molecule interactions. Here we describe a new approach for obtaining structural information on small molecules bound in the hydrophobic pocket of gp41, using a paramagnetic probe peptide which binds adjacent to the pocket along an extended coiled coil. Ligand binding in the pocket leads to paramagnetic relaxation effects or pseudocontact shifts of ligand protons. These effects are distance and / or orientation dependent, permitting determination of ligand pose in the pocket. The method is demonstrated with a fast-exchanging ligand. Multiple measurements at different coiled coil and probe peptide ratios enabled accurate determination of the NMR parameters. Use of a labeled probe peptide stabilizes an otherwise aggregation-prone coiled coil, and also enables modulation of the paramagnetic effect to study ligands of various affinities. Ultimately, this technique can provide essential information for structure-based design of non-peptide fusion inhibitors.
PMCID: PMC2880620  PMID: 19206471
6.  Effects of Transdermal Estrogen Therapy on Expressions of Estrogen Receptors and T-lymphocyte Apoptosis in Surgically Menopausal Women 
Studies have demonstrated estrogen replacement therapy can improve the life quality of surgically menopausal women. However, the mechanisms in this process remain poorly defined. Here we show the effect of transdermal estrogen therapy on expressions of estrogen receptors and T-lymphocyte apoptosis in surgically postmenopausal women. Fifteen surgically menopausal women, 15 naturally menopausal women and 15 young women were chosen in our studies. Peripheral vein blood was collected and serum E2 and FSH levels were assessed using ACCESS. T-lymphocyte apoptosis and the expressions of Fas, FasL and ER subtypes α and β were determined. The serum E2 levels of surgically menopausal woman were significantly higher, and the “Improved Kupperman Index” and the scores of “Menopause Specific Quality of Life Questionnaire” in surgically menopausal women were significantly low after ERT. The rates of T-lymphocyte apoptosis and FasL expression in surgically menopausal women were decreased after ERT, but the difference was not significant. The expressions of ERα and ERβ in two menopausal groups were significantly lower than those of the young group. They were both significantly up-regulated after 3 months of ERT. Transdermal ERT could significantly upregulate the serum E2 level, could improve menopausal symptoms and life quality of surgically menopausal women and upregulate ERα and ERβ expressions on T lymphocytes, especially ERβ. Thus, the low dose of transdermal ERT may have a protective effect on menopausal women's immune function and aging.
PMCID: PMC4002719  PMID: 19728929
estrogen replacement therapy; surgical menopause; estrogen receptor; T-lymphocyte apoptosis

Results 1-6 (6)