A β‑Boronopeptide Bundle of Known Structure As a Vehicle for Polyol Recognition

Despite significant progress in the design of receptors and sensors for simple polyols and monosaccharides, few synthetic receptors discriminate among multiple saccharide units simultaneously, especially under physiological conditions. Described here is the three-dimensional structure of a supramolecular complexa β-peptide bundledesigned for the potential to interact simultaneously with as many as eight discrete monosaccharide units. The preliminary evaluation of this construct as a vehicle for polyol binding is also presented

Human Microbiome Inspired Antibiotics with Improved β‑Lactam Synergy against MDR <i>Staphylococcus aureus</i>

The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin <b>17S</b>. Compared to humimycin A, <b>17S</b> is a more potent β-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant <i>Staphylococcus aureus</i> (MRSA) and vancomycin resistant <i>Enterococcus faecalis</i> (VRE), and did not lead to any detectable resistance when used in combination with a β-lactam. Combinations of β-lactam and humimycin <b>17S</b> provide a potentially useful long-term MRSA regimen

Clinical response based on assessment of skin biopsies and PASI and PGA.

<p>Clinical response based on assessment of skin biopsies and PASI and PGA.</p

<i>Ex vivo</i> stimulation of whole blood drawn 2h post 70mg dose as compared to the pre-dose in cytokine production.

<p>Whole blood drawn pre-dose and 2h post 70mg dose (<i>n</i>  =  10) were stimulated with 0.1% SAC within 24h of the draw, and the supernatants were analyzed for IL-12p70 (a), IL-10 (b), and GM-CSF (c). *, <i>p</i> ≤0.05; statistically significant differences between pre- and 2h post-dose.</p

The HSP90 Inhibitor Ganetespib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRL/lpr Mouse Model of Systemic Lupus Erythematosus

<div><p>Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease with a diverse range of immunological and clinical manifestations. The introduction of broad spectrum immunosuppressive therapies and better management of acute disease exacerbations have improved outcomes for lupus patients over recent years. However, these regimens are burdened by substantial toxicities and confer significantly higher risks of infection, thus there remains a significant and unmet medical need for alternative treatment options, particularly those with improved safety profiles. Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperone that acts as an important modulator of multiple innate and adaptive inflammatory processes. Of note, accumulating clinical and experimental evidence has implicated a role for HSP90 in the pathogenesis of SLE. Here we evaluated the potential of HSP90 as a therapeutic target for this disease using the selective small molecule inhibitor ganetespib in the well-characterized MRL/lpr autoimmune mouse model. In both the prophylactic and therapeutic dosing settings, ganetespib treatment promoted dramatic symptomatic improvements in multiple disease parameters, including suppression of autoantibody production and the preservation of renal tissue integrity and function. In addition, ganetespib exerted profound inhibitory effects on disease-related lymphadenopathy and splenomegaly, and reduced pathogenic T and B cell lineage populations in the spleen. Ganetespib monotherapy was found to be equally efficacious and tolerable when compared to an effective weekly dosing regimen of the standard-of-care immunosuppressive agent cyclophosphamide. Importantly, co-treatment of ganetespib with a sub-optimal, intermittent dosing schedule of cyclophosphamide resulted in superior therapeutic indices and maximal disease control. These findings highlight the potential of HSP90 inhibition as an alternative, and potentially complementary, strategy for therapeutic intervention in SLE. Such approaches may have important implications for disease management, particularly for limiting or preventing treatment-related toxicities, a major confounding factor in current SLE therapy.</p></div

Histological improvement by apilimod treatment.

<p>Histology and immunohistochemistry of one patient (1046) showing improved histology and clinical measures (58%reduction in PASI score) at week 12 in the 70mg QD apilimod treated group. Skin biopsies from non-lesions (left) and lesions (middle) at baseline and lesion at week 12 (right) were stained with H&E, K16, anti-CD3 Ab, anti-CD11c Ab, or anti- IL-12p40 Ab. Cells staining positive for CD3, CD11c and IL-12p40 are indicated (arrows).</p

Cellular phenotype in normal controls and psoriasis patients before and after 70mg QD treatment.

<p>Whole blood cells from normal controls and psoriasis patients were analyzed by cytometry for the cellular phenotype. Results shown are the percentile ranges based on cell counts (cells/µL) of peripheral CD4⁺ T cells, CD8⁺ T cells, B cells, monocytes, eosinophils and neutrophils from normal controls (<i>n</i>  =  16) and psoriasis patients in 70mg QD cohort (<i>n</i>  =  12) at baseline (week 0) and week 12. Plot: bottom line, 10^th%; bottom box, 25^th%; top box, 75^th%; top line, 90^th%. *, <i>p</i> < 0.05; **, <i>p</i> <0.01; statistically significant differences between before (week 0) and after (week 12) 70mg QD apilimod treatment in psoriasis patients.</p

Changes in the expression levels of IL-12/IL-23p40, IL-23p19, and IL-10 at week 2 in 70mg QD apilimod cohort.

<p>RNA was prepared from biopsies obtained from the psoriatic skin lesions at baseline (week 0) and week 2, and RT-PCR was performed for IL-12/IL-23p40 (a), IL-23p19 (b), and IL-10 (c). The expression levels were normalized to house keeping gene, hARP. Results shown are the expression levels of individuals in 70mg QD cohort (<i>n</i>  =  11, 3 histological responders, 8 histological non-responders). *, <i>p</i> ≤0.05; **, <i>p</i> ≤0.01; statistically significant differences between baseline and week 2.</p

Mean skin-infiltrating T cell and dendritic cell numbers.

1<p>Mean cell numbers of epidermal CD3⁺ (T cell) cells, dermal CD3⁺ cells, epidermal CD11c⁺ (dendritic cell) cells, and dermal CD11c⁺ cells per low-power field during treatment, with patients classified by response. There were 17 responders and 30 non-responders in the analysis.</p

<i>In vitro</i> effect of apilimod on IL-12p70, IL-10, GM-CSF, and IL-6 in human whole blood cells.

<p>Human whole blood from a normal volunteer was stimulated with 0.1% SAC in the presence of different concentrations of apilimod. Supernatants were tested for IL-12p70 (circles), IL-10 (triangles), GM-CSF (diamonds) and IL-6 (squares). Results are representative of one of three individual experiments with whole blood from different volunteers each time.</p