3D-QSAR Studies on Thiazolidin-4-one S1P1 Receptor Agonists by CoMFA and CoMSIA

Selective S1P1 receptor agonists have therapeutic potential to treat a variety of immune-mediated diseases. A series of 2-imino-thiazolidin-4-one derivatives displaying potent S1P1 receptor agonistic activity were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q2 value of 0.751 and an r2 value of 0.973, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic, hydrophobic and H-bond donor descriptors, predicted a q2 value of 0.739 and an r2 value of 0.923. The models were graphically interpreted using contour plots which gave more insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active S1P1 receptor agonists

Linker-extended native cyanovirin-N facilitates PEGylation and potently inhibits HIV-1 by targeting the glycan ligand

Cyanovirin-N (CVN) potently inhibits human immunodeficiency virus type 1 (HIV-1) infection, but both cytotoxicity and immunogenicity have hindered the translation of this protein into a viable therapeutic. A molecular docking analysis suggested that up to 12 residues were involved in the interaction of the reverse parallel CVN dimer with the oligosaccharide targets, among which Leu-1 was the most prominent hot spot residue. This finding provided a possible explanation for the lack of anti-HIV-1 activity observed with N-terminal PEGylated CVN. Therefore, linker-CVN (LCVN) was designed as a CVN derivative with a flexible and hydrophilic linker (Gly4Ser)3 at the N-terminus. The N-terminal α-amine of LCVN was PEGylated to create 10 K PEG-aldehyde (ALD)-LCVN. LCVN and 10 K PEG-ALD-LCVN retained the specificity and affinity of CVN for high mannose N-glycans. Moreover, LCVN exhibited significant anti-HIV-1 activity with attenuated cytotoxicity in the HaCaT keratinocyte cell line and MT-4 T lymphocyte cell lines. 10 K PEG-ALD-LCVN also efficiently inactivated HIV-1 with remarkably decreased cytotoxicity and pronounced cell-to-cell fusion inhibitory activity in vitro. The linker-extended CVN and the mono-PEGylated derivative were determined to be promising candidates for the development of an anti-HIV-1 agent. This derivatization approach provided a model for the PEGylation of biologic candidates without introducing point mutations. © 2014 Chen et al

Associations between TNF-alpha-308A/G Polymorphism and Susceptibility with Dermatomyositis: A Meta-Analysis

Background: Some surveys had inspected the effects of the tumor necrosis factor-alpha (TNF-alpha)-308A/G polymorphism on susceptibility to dermatomyositis (DM), and showed mixed results. To briefly review these consequences, a comprehensive meta-analysis was carried out to estimate the relationship between them much more accurately

Associations between TNF-α-308A/G Polymorphism and Susceptibility with Dermatomyositis: A Meta-Analysis

<div><p>Background</p><p>Some surveys had inspected the effects of the tumor necrosis factor-α (TNF-α)-308A/G polymorphism on susceptibility to dermatomyositis (DM), and showed mixed results. To briefly review these consequences, a comprehensive meta-analysis was carried out to estimate the relationship between them much more accurately.</p><p>Methods</p><p>Relevant documents dated to February 2014 were acquired from the PUBMED, MEDLINE, and EMBASE databases. The number of the genotypes and/or alleles for the TNF-α-308A/G in the DM and control subjects was extracted and statistical analysis was conducted using STATA 11.2 software. Summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) were used to calculate the risk of DM with TNF-α-308A/G. Stratified analysis based on ethnicity and control population source was also performed.</p><p>Results</p><p>555 patients with DM and 1005 controls from eight published investigations were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the TNF-α-308A allele were 2.041 (95% CIs 1.528–2.725, P<0.0001) in DM. Stratification by ethnicity indicated the TNF-α-308A allele polymorphism was found to be significantly associated with DM in Europeans (OR = 1.977, 95% CI 1.413–2.765, P<0.0001). The only study conducted on TNF-α-308A/G polymorphism in Asians could not be used in ethnicity-stratified meta-analysis. Meta-analysis of the AA+AG vs. GG (dominant model) and AA vs. GG (additive model) of this polymorphism revealed a significant association with DM in overall populations and Europeans.</p><p>Conclusions</p><p>Our meta-analysis demonstrated that the TNF-α-308A/G polymorphism in the TNF gene might contribute to DM susceptibility, especially in European population. However, further studies with large sample sizes and among different ethnicity populations should be required to verify the association.</p></div

Genetic Association Study of <i>TNFAIP3</i>, <i>IFIH1</i>, <i>IRF5</i> Polymorphisms with Polymyositis/Dermatomyositis in Chinese Han Population

<div><p>Background</p><p>Single-nucleotide polymorphisms (SNPs) in the <i>TNFAIP3</i>, <i>IFIH1</i>, and <i>IRF5</i> genes have been associated with several auto-inflammation diseases, while the susceptibility between these genes and idiopathic inflammatory myopathies (IIMs) were not reported. This study aimed to investigate whether <i>TNFAIP3</i>, <i>IFIH1</i>, and <i>IRF5</i> gene polymorphisms confer susceptibility for the IIMs in Chinese Han population.</p><p>Methods</p><p>A large case–control study of Chinese subjects with polymyositis (PM) (n = 298) and dermatomyositis (DM) (n = 530) was accomplished. 968 healthy and ethnically matched controls were available for comparison. Six SNPs in the <i>TNFAIP3</i> region (rs2230926 and rs5029939), the <i>IFIH1</i> gene (rs1990760 and rs3747517) and the <i>IRF5</i> region (rs4728142 and rs729302) were assessed and genotyped using the Sequenom MassArray iPLEX platform.</p><p>Results</p><p>Our study indicated a strong allele association was observed in PM/DM and PM patients for rs2230926 (OR: 1.61, 95%CI: 1.20–2.16, <i>P_c</i> = 7.5×10⁻³; OR: 1.88, 95%CI: 1.30–2.74, <i>P_c</i> = 4.0×10⁻³, respectively) and rs5029939 (OR: 1.64, 95%CI: 1.21–2.21, <i>P_c</i> = 6.0×10⁻³; OR: 1.88, 95%CI: 1.28–2.76, <i>P_c</i> = 5.5×10⁻³,respectively). And rs2230926 and rs5029939 were significantly associated with interstitial lung disease (ILD) in PM/DM and PM patients (<i>P_c</i> = 0.04 and <i>P_c</i> = 0.016; <i>P_c</i> = 0.02 and <i>P_c</i> = 0.03, respectively). In addition, rs4728142 allele and genotype had significant association with PM/DM patients (<i>P_c</i> = 0.026 and <i>P_c</i> = 0.048, respectively). Further analysis with three logistic regression genetic models revealed statistically significant difference in the genotypic distribution in the PM/DM, PM or DM patients when the additive and dominant models were used.</p><p>Conclusions</p><p>This was the first study to reveal <i>TNFAIP3</i> and <i>IRF5</i> polymorphisms were associated with PM/DM patients or these patients with ILD, indicating that <i>TNFAIP3</i> and <i>IRF5</i> might be the susceptibility gene for PM/DM patients in Chinese Han population.</p></div

Clinical data for PM/DM patients and controls.

<p>PM: polymyositis; DM: dermatomyositis; ILD: interstitial lung disease.</p><p>Clinical data for PM/DM patients and controls.</p

Characteristics of the studies and populations included in the meta-analysis.

<p>Author: first author’s name, <i>Ref:</i> reference; Year: Publication year; USA: United States of America, UK: United Kingdom, E: European, A: Asian; SOC: source of control, HB: hospital-based, PB: population-based; NS no significant; P_HWE: P value of Hardy-Weinberg equilibrium, chi-square test; *Power calculations assume α = 0.05, OR = 1.5.</p

Forest plot of the susceptibility of DM associated with TNF-α-308 gene polymorphism under stratification.

<p>A: A vs. G, Forest plot; B: AA+AG vs. GG, Forest plot, C: AA vs. GG, D: AA vs. GG+AG.</p

Meta-analysis of the association between the TNF-α-308 A/G polymorphism and DM.

<p>OR odds ratio; CI confidence interval; F fixed effects model; R random effects model; NA not available.</p

Begg’s funnel plot for publication bias test (AA vs. GG).

<p>Begg’s funnel plot for publication bias test (AA vs. GG).</p