Disease relevance of MURABUTIDE

• In this study, we have examined the ability of Murabutide to control HIV type 1 (HIV-1) replication in acutely infected monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) [1].
• The synthetic immunomodulator murabutide controls human immunodeficiency virus type 1 replication at multiple levels in macrophages and dendritic cells [1].
• The present study was designed to profile the activity of Murabutide on CD8-depleted phytohemagglutinin-activated lymphocytes from HIV-1-infected subjects and on the outcome of HIV-1 infection in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) [2].
• The present experiments were designed to test the immunogenicity of the peptide when attached to a tetanus toxoid carrier and administered with alum or murabutide, both acceptable clinical adjuvants [3].
• Enhancement by murabutide of the immune response to natural and synthetic hepatitis B surface antigens [4].

High impact information on MURABUTIDE

• We have previously observed that the synthetic immunomodulator Murabutide inhibits human immunodeficiency virus type 1 (HIV-1) replication at multiple levels in macrophages and dendritic cells [2].
• Moreover, c-myc mRNA expression was down-regulated in Murabutide-treated cells, suggesting potential interference of the immunomodulator with the nuclear transport of viral preintegration complexes [2].
• Maintaining cultures of CD8-depleted blasts from 36 patients in the presence of Murabutide produced dramatically reduced levels of viral p24 protein in the supernatants [2].
• Furthermore, Murabutide-stimulated cells expressed reduced CD4 and CCR5 receptors and secreted high levels of beta-chemokines, although neutralization of the released chemokines did not alter the HIV-1-suppressive activity of Murabutide [1].
• Murabutide is a safe synthetic immunomodulator presenting a capacity to enhance nonspecific resistance against viral infections and to target cells of the reticuloendothelial system [1].

Biological context of MURABUTIDE

• Cell-mediated immunity to HBsAg, tested by the proliferative response of lymph node cells to the antigen, was also shown to be induced in mice treated with alum-associated murabutide [4].
• Moreover, changes in several immune parameters, including downregulation of coreceptor expression on lymphocytes and improved lymphoproliferative responses, were detected during or/and up to 3 weeks after Murabutide administration [5].
• The safe synthetic immunomodulator Murabutide (ISTAC Biotechnology, Lille, France) has been found to regulate the function of antigen-presenting cells and to selectively activate CD4 lymphocytes leading to dramatic suppression of HIV replication, in vitro [5].
• Interestingly, in comparison with pre-inclusion levels, at 1 week after the immunotherapy cycle, only murabutide recipients presented a significant increase in CD4 cells, platelet counts, and in the percentage of patients with undetectable viral loads (<50 copies/mL) [6].
• Clinical and immunological effects of a 6 week immunotherapy cycle with murabutide in HIV-1 patients with unsuccessful long-term antiretroviral treatment [6].

Anatomical context of MURABUTIDE

• It was concluded that the enhancement induced by the adjuvants LPS, poly(A)-poly(U), and murabutide is mediated in part by their action on T cells resulting in release of IFN-gamma suggesting activation of a common transmembrane signal [7].
• When saline was used, low levels of thyroid infiltration were observed in a few of the MDP-treated animals in only one experiment, whereas no lesions were observed when murabutide was used [8].
• In vivo suppression of the immune response to sheep erythrocytes was also observed with high doses of murabutide, a nonpyrogenic adjuvant-active N-acetylmuramyl-L-alanyl-D-isoglutamine analog [9].
• Among the synthetic glycopeptides inducing the production of D factor, murabutide (MDP[Gln]-OnBu) was as effective as MDP, although it did not stimulate monocytes to simultaneously release endogenous pyrogen [10].
• Two adjuvant-active peptides (MDP and Murabutide) induced CSA in the supernatant of cultured endothelial cells, whereas an adjuvant-inactive compound had no effect [11].

Associations of MURABUTIDE with other chemical compounds

• One of the MDP derivatives used in the conjugates was epsilon-amino-caproic Murabutide, since Murabutide which is currently in clinical trials cannot be conjugated [12].
• In this study we sought to identify how soluble forms of M. leprae antigen(s) or particulate (liposome) delivery of the same antigens with two immunomodulators Murabutide and T cell peptide of Trat protein influence the transcription of IL-2 gene in anergic T cells of lepromatous patients [13].

Gene context of MURABUTIDE

• These preclinical findings will be pursued by the evaluation of the clinical tolerance and biologic activity of the murabutide/IL-2 combination therapy in cancer patients [14].
• Macrophage stimulation with Murabutide, an HIV-suppressive muramyl peptide derivative, selectively activates extracellular signal-regulated kinases 1 and 2, C/EBPbeta and STAT1: role of CD14 and Toll-like receptors 2 and 4 [15].
• Although neither IL-12 nor IFN-gamma were produced in cells stimulated with murabutide alone, some mRNA expression was found with combined treatments [16].
• IL-3 and GM-CSF were more potent in increasing the murabutide-induced response, eliciting synergistic effects on IL-8 and IL-1Ra production, at both the mRNA accumulation and the protein release [16].
• We recently showed, in vitro and in vivo, a synergistic activity between the synthetic immunomodulator murabutide, which is in clinical stage of development, and another therapeutic cytokine, interferon-alpha (IFN-alpha) [14].

Analytical, diagnostic and therapeutic context of MURABUTIDE

• The use of tetanus toxoid in secondary immunizations could be eliminated when the mice primed with peptide-tetanus toxoid and murabutide were boosted with a polymer of the peptide [3].
• These encouraging results warrant further evaluation of longer periods or cycles of immunotherapy with Murabutide in HIV-infected subjects [5].
• Therefore, as a first step toward the evaluation of the immunotherapeutic potential of Murabutide in HIV disease, we have conducted two phase 1/2 clinical trials to address the safety and the immunologic effects of Murabutide administration into HIV-infected subjects receiving antiretroviral therapy [5].
• These results warrant further evaluation of extended periods or cycles of murabutide immunotherapy as adjunct to HAART [6].
• Administration of murabutide was generally well tolerated, although some grade III adverse events, reversible on treatment cessation, were observed [6].

References