Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies

VanPatten, Sonya; Sun, Shan; He, Mingzhu; Cheng, Kai; Altiti, Ahmad S.; Papatheodorou, Angelos; Kowal, Czeslawa; Jeganathan, Venkatesh; Crawford, James M.; Bloom, Ona; Volpe, Bruce T.; Grant, Christian; Meurice, Nathalie; Coleman, Thomas R.; Diamond, Betty; Al‐Abed, Yousef

doi:10.1021/acs.jmedchem.6b00694

Cited by 13 publications

(11 citation statements)

References 37 publications

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“…FISLE-412 can reduce glomerular deposition of IgG, protect kidneys from damage, and suppress the onset of SLE in murine models. Moreover, the FISLE-12-bound anti-dsDNA antibodies exert no neurotoxic effects on C57BL/6 mice; this finding shows a greater neuroprotective effect than that of the DWEYS peptide (136). As compared with DWEYS, FISLE-412 has higher affinity and a more stable structure and is more suitable for oral administration (136).…”

Section: The Blockade Of Pathogenic Anti-dsdna Iggmentioning

confidence: 87%

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Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

2019

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Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.

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Section: The Blockade Of Pathogenic Anti-dsdna Iggmentioning

confidence: 87%

“…FISLE-412, an analog of a reduced protease inhibitor for the human immunodeficiency virus, has the potential to block DNA recognition of anti-dsDNA antibodies (136). FISLE-412 can reduce glomerular deposition of IgG, protect kidneys from damage, and suppress the onset of SLE in murine models.…”

Section: The Blockade Of Pathogenic Anti-dsdna Iggmentioning

confidence: 99%

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

2019

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“…However, repeated dosing with BPI could also enhance BPI-ANCA production, diminishing BPI potency and exacerbating immune complex-mediated inflammation. Potentially, this may be alleviated by the use of small molecule decoys, peptidomimetics of BPI structural motifs, to neutralise the corresponding ANCAs (Vanpatten et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Targeting IgG Autoantibodies for Improved Cytotoxicity of Bactericidal Permeability Increasing Protein in Cystic Fibrosis

et al. 2020

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In people with cystic fibrosis (PWCF), inflammation with concurrent infection occurs from a young age and significantly influences lung disease progression. Studies indicate that neutrophils are important effector cells in the pathogenesis of CF and in the development of anti-neutrophil cytoplasmic autoantibodies (ANCA). ANCA specific for bactericidal permeability increasing protein (BPI-ANCA) are detected in people with CF, and correlate with infection with Pseudomonas aeruginosa. The aim of this study was to determine the signaling mechanism leading to increased BPI release by CF neutrophils, while identifying IgG class BPI-ANCA in CF airways samples as the cause for impaired antimicrobial activity of BPI against P. aeruginosa. Plasma and/or bronchoalveolar lavage fluid (BAL) was collected from PWCF (n = 40), CF receiving ivacaftor therapy (n = 10), non-CF patient cohorts (n = 7) and healthy controls (n = 38). Plasma and BAL BPI and BPI-ANCA were measured by ELISA and GTP-bound Rac2 detected using an in vitro assay. The antibacterial effect of all treatments tested was determined by colony forming units enumeration. Levels of BPI are significantly increased in plasma (p = 0.007) and BALF (p < 0.0001) of PWCF. The signaling mechanism leading to increased degranulation and exocytosis of BPI by CF neutrophils (p = 0.02) involved enhancement of Rac2 GTPloading (p = 0.03). The full-length BPI protein was detectable in all CF BAL samples and patients displayed ANCA with BPI specificity. IgG class autoantibodies were purified from CF BAL complexed to BPI (n=5), with IgG autoantibody cross-linking of antigen preventing BPI induced P. aeruginosa killing (p < 0.0001). Results indicate that the immune-mediated diminished antimicrobial defense, attributed to anti-BPI-IgG, necessitates the formation of a drug/immune complex intermediate that can maintain cytotoxic effects of BPI towards Gram-negative pathogens, with the potential to transform the current treatment of CF airways disease.

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“…Next, we turned our attention to explore the utility of this protocol in asymmetric synthesis by building the novel peptidomimetic FISLE‐412 ; a potent polyamine neutralizes anti ‐dsDNA/NMDAR lupus autoantibodies and prevents their pathogenic interaction with tissue antigens . This polyamine is very challenging in terms of synthesis, resolution and purification, the only access to this molecule was through global reduction of the corresponding peptide “Saquinavir”, this reduction process was very tedious and gave an inseparable mixture of FISLE‐412 with very low yield after multiple purifications .…”

Section: Figurementioning

confidence: 99%

β‐Hydroxy‐tetrahydroquinolines from Quinolines Using Chloroborane: Synthesis of the Peptidomimetic FISLE‐412

Altiti

Cheng

et al. 2017

Chemistry A European J

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A new synthetic protocol provides a simple and direct method to generate functionalized β-hydroxy-tetrahydroquinolines (THQs). Hydroboration of quinolines using chloroboranes followed by oxidation led to the formation of functionalized β-hydroxy-tetrahydroquinolines. High regio and diastereoselectivities were observed in α or γ substituted quinolines and the trans diastereomer of β-hydroxy-THQ was the major isostere. This new protocol was utilized to build the novel antibody-targeted lupus peptidomimetic FISLE-412.

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Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies

Cited by 13 publications

References 37 publications

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

Targeting IgG Autoantibodies for Improved Cytotoxicity of Bactericidal Permeability Increasing Protein in Cystic Fibrosis

β‐Hydroxy‐tetrahydroquinolines from Quinolines Using Chloroborane: Synthesis of the Peptidomimetic FISLE‐412

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