SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor

We describe structure–activity relationship and optimization studies of RN-18, an HIV-1 Vif-APOBEC3G axis inhibitor. Targeted modifications of RN-18 ring C, ring B, ring A, bridge A–B, and bridge B–C were performed to identify the crucial structural features, which generated new inhibitors with similar (<b>4g</b> and <b>4i</b>) and improved (<b>5</b>, <b>8b</b>, and <b>11</b>) activities. Two potent water-soluble RN-18 analogues, <b>17</b> and <b>19</b>, are also disclosed, and we describe the results of pharmacological studies with compound <b>19</b>. The findings described here will be useful in the development of more potent Vif inhibitors and in the design of probes to identify the target protein of RN-18 and its analogues

1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV‑1 Vif Antagonists

RN-18 based viral infectivity factor (Vif), Vif antagonists reduce viral infectivity by rescuing APOBEC3G (A3G) expression and enhancing A3G-dependent Vif degradation. Replacement of amide functionality in RN-18 (IC₅₀ = 6 μM) by isosteric heterocycles resulted in the discovery of a 1,2,3-trizole, <b>1d</b> (IC₅₀ = 1.2 μM). We identified several potent HIV-1 inhibitors from a <b>1d</b> based library including <b>5ax</b> (IC₅₀ = 0.01 μM), <b>5bx</b> (0.2 μM), <b>2ey</b> (0.4 μM), <b>5ey</b> (0.6 μM), and <b>6bx</b> (0.2 μM)

Piqueria trinervia

原著和名: ステビア科名: キク科 = Compositae採集地: 千葉県 船橋市三山2-2-1 東邦大学 (下総 東邦大学)採集日: 1974/9/26採集者: 萩庭丈壽整理番号: JH025454国立科学博物館整理番号: TNS-VS-97545

MOESM1 of Lack of concordance between residual viremia and viral variants driving de novo infection of CD4+ T cells on ART

Additional file 1: Figure S1. Sorting strategy used to purify the different CD4+ T-cell subsets

Association between <i>PSIP1</i> haplotypes and AIDS progression.

<p>Results are shown as OR (95% confidence interval; p-value). LTNP  =  long-term nonprogressors, TP  =  typical progressors and RP  =  rapid progressors. n.d.  =  not done.</p

General characteristics of the subjects according to the study group and clinical classification.

<p>*Age at sample collection for population controls (HIV−) and at first positive test for HIV+ patients.</p><p>**Results are shown as N (frequency).</p><p>***p<0.05 for ethnicity comparisons according to χ² test. LTNP  =  long-term nonprogressors, TP  =  typical progressors and RP  =  rapid progressors.</p

Association between <i>PSIP1</i> SNPs and AIDS progression.

<p>Results are shown as OR (95% confidence interval; p-value) estimated under a codominant model. LTNP  =  long-term nonprogressors, TP  =  typical progressors and RP  =  rapid progressors. n.d  =  not determined.</p

LEDGF/p75 genomic organization and structure.

<p>A) <i>PSIP1</i> gene organization: Exons are represented as grey blocks and numbered according to their position in the chromossome. 5′ UTR and 3′UTR are indicated by black blocks. Introns are represented by black lines. The SNPs analyzed in the present study are indicated by arrows according to their genomic position. *rs2277191 is located in a non coding region between the two <i>PSIP1</i> 5′UTR regions. B) Protein structure: LEDGF/p75 protein domains are represented: PWWP (proline-tryptophan-tryptophan-proline domain); NLS (nuclear localization signal); AT hook (adenine-thymine rich DNA binding region) and IBD (integrase binding domain). The positions associated to the interaction with HIV-1 integrase (K364, I365, D366, F406, V408) and the positions I436 and I473 previously described to present rare missense mutations in LTNPs (Ballana et al., 2012) were investigated in this study.</p

Schematic representation of IntegRal and Discor-Ral studies.

<p>In both studies, enrolled individuals were randomized 1∶2 to continue with previous cART (Ctrol, control groups in orange) or intensify their therapy with raltegravir (+Ral, intensified groups in blue). The extent of raltegravir intensification was 48 weeks for the IntegRal study and 72 weeks for the Discor-Ral study (grey areas). The follow up of the IntegRal study was 60 weeks, allowing for the analysis of the effect of raltegravir discontinuation. In the Discor-Ral study six patients from the control arm started raltegravir for 24 weeks (blue area). In all groups, asterisks denote sampling times.</p

Baseline characteristics of the control and raltegravir-intensified individuals.

<p>PI, protease inhibitors; ART, antiretroviral treatment; VL, plasma viral load (HIV-1 RNA copies/ml);</p><p>a p-value between groups: Mann-Whitney U test,</p><p>b p-value of the comparison of patients enrolled in the IntegRal (n = 67) and DIscor-Ral (n = 44) studies: Mann-Whitney U test.</p><p>Baseline characteristics of the control and raltegravir-intensified individuals.</p