LK-409 (7-oxooctanoyl-L-Ala-D-iGln) was found to modulate immune response. To study the impact of minimal structural changes in the LK-409 molecule on the immunomodulatory activity a series of LK-409 analogues was prepared and their activities were evaluated. After the treatment of NmRI mice at a dose of 25 microg daily for three consecutive days the isolated spleen cells were stimulated with concanavaline A and phorbol 12-myristate 13-acetate (PMA) or ionomycin and PMA, and the production of IL-2, IL-4,-IL-6, IL-10 and IFN-gamma studied as a function of the different LK-409 analogues. All the compounds modulate the Th1/Th2 cytokine response, especially in the presence of ConA&PMA activation. The minimal structure modification of LK-409 strongly influences the regulation of the cytokine production.

01 Jan 2000·Pflügers Archiv - European Journal of Physiology

Modulation of tumour necrosis factor production with desmuramyldipeptide analogues

Article

Author: Urleb, Uroš ; Gobec, Stanislav ; Sollner, Marija ; Simčič, Saša ; Wraber, Branka

Some synthetic analogues of the immuno-modulatory agent muramyl dipeptide (MDP), i.e. phthalimido- (LK-511, LK-413, LK-512, LK-423, LK-508), adamantyl- (LK-415, LK-517), 7-oxoaIkyl-(LK-409) desmuramylpeptides were assessed for the tumour necrosis factor (TNF) inducing activity and the ability to modulate TNF production in in vitro phorbol 12-myristate 13-acetate (PMA) & ionomycin stimulated cultures of human peripheral blood mononuclear cells. A kinetic study over a 40-hour period indicated that desmuramyldipeptides were weak TNF inducers compared to romurtide, PMA & ionomycin or lipopolysaccharide. By contrast, they showed the potential to up- or down-regulate the production of TNF evoked by PMA & ionomycin, which was strongly dependent on the time of the stimulation. After 4h of stimulation, the TNF secretion was augmented by LK-508, LK-409 and LK-511, after 18 h by LK-409 and LK-423, and after 40 h by LK-423, LK-511, LK-415 and LK-512. However, LK-517 and LK-512 inhibited the secretion of TNF after the 18-h period.

01 Nov 1996·Pflügers Archiv European Journal of Physiology

Potential therapeutic indications for synthetic desmuramyl MDP analogue (LK-409)

Article

Author: V. Kotnik ; A. Štalc

Synthetic desmuramyl analogues are potentially immunostimulating drugs. Until today a lot of different molecules were constructed, some with interesting augmenting properties, but most of them with unpleasant pyrogenic side effects. LK-409, 7-oxooctanoyl-L-alanyl-D-isoglutamine, synthesised at the Pharmaceutical faculty of Ljubljana, is an apyrogenic derivative with promising immunostimulating activity. LK-409 and the control substance romurtide were tested for more than 50 parameters. All the immune response levels were included in the study; the development and proliferation of stem cells from bone marrow, the natural defence mechanisms with special regard to the function of phagocytic cells, the humoral immune response with special regard to the development of plaque forming cells and the cellular immune response with regard to the proliferating ability of the immune cells and production of regulating and differentiating cytokines, in vitro and in vivo. Results of LK-409 and romurtide activity were sorted in six groups, and evaluated. The analysis shows that LK-409 affects the measured parameters more efficiently than does romurtide. The most pronounced effect was stimulation of the immune response in drug and tumor induced immunosuppression.

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Indication	Highest Phase	Country/Location	Organization	Date
Immunologic Deficiency Syndromes	Preclinical	US	-	-
Immunologic Deficiency Syndromes	Preclinical	JP	-	-
Immunologic Deficiency Syndromes	Preclinical	SI	Lek Pharmaceuticals dd	-
Immunologic Deficiency Syndromes	Preclinical	SI	University of Ljubljana	-
Neoplasms	Preclinical	SI	University of Ljubljana	-
Neoplasms	Preclinical	SI	Lek Pharmaceuticals dd	-

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