Cyclic tetrapeptides and therapeutic applications thereof
a technology of tetrapeptides and tetrapeptides, applied in the direction of tetrapeptides, cyclic peptides, cyclic peptide ingredients, etc., can solve the problems of serious challenge to medicinal chemistry, undesirable side effects, and high production costs of these drugs, so as to reduce the toxic effect the effect of lowering the toxicity profile of a second drug
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example 1
Synthesis of Cyclic Tetrapeptides
[0105]Cyclic tetrapeptides according to embodiments of the invention can be synthesized by the use of known peptide synthesis methods, such as solution-phase or solid-phase methods. In general the synthesis involves two consecutive steps: (1) synthesis of a linear tetrapeptide and (2) cyclization to yield the cyclic tetrapeptide. The linear tetrapeptide may be prepared in protected form and then deprotected prior to cyclization.
[0106]To illustrate, the synthesis of linear tetrapeptides on a solid support (Fmoc-L-phenylalanine attached to a Wang-type resin, or either L-beta-3-homophenylalanine or L-proline attached to a 2-chloro trityl resin) was conducted according to the following protocol:
1. The resin was swelled in dimethylformamide (DMF) (0.25 mmol, 10 ml / g resin) for 15 min.
2. The Fmoc group was removed with a 20% solution of piperidine in DMF (2×20 min).
3. The resin was washed with DMF (3×2 min)
4. The resin was washed with methanol (MeOH) (3×2 ...
example 2
Therapeutic Efficacy of the Peptide as a 0.1% Ointment in the Model of Contact Sensitivity to Oxazolone in BALB / c Mice
[0116]The aim of this experiment was to verify the therapeutic action of compound I-A and its toxicity in a generally accepted animal model. In the experiment described below, the compound of formula I-A was applied as a therapeutic preparation in the form of 0.1% wt / wt ointment based on a commonly used pharmaceutical vehicle, namely an ointment composed of 50% vaseline and 50% lanoline. The usefulness of the preparation in reduction of the effector phase of the contact sensitivity to oxazolone in mice, in comparison with reference preparations such as tacrolimus (Protopic®) and pimecrolimus (Elidel®), widely used for treatment of skin diseases, was studied.
Materials and Methods
[0117]Mice: BALB / c female mice, 8-10 week-old, delivered by the Institute of Laboratory Medicine, ódź, Poland, were used for the study. The mice were fed a commercial, pelleted food and water ...
example 3
The Toxicity of Compound I-A Versus that of Cyclolinopeptide Against Human Blood Mononuclear Cells
[0135]For evaluation of toxicity of the compound of formula I-A, human peripheral mononuclear blood cells (PBMC) were chosen. This fraction consists of approximately 80% lymphocytes and 20% monocytes. As a reference compound, cyclolinopeptide (CLA) was selected since the compound of formula I-A shares a part of the sequence of CLA. CLA exhibits immunosuppressive properties comparable to that of cyclosporine A, but is less toxic.
Materials and Methods
[0136]The Cytotoxic Test:
[0137]Venous blood from a single donor was taken into heparinized syringes, diluted twice with phosphate buffered saline (PBS) and applied onto Lymphoprep® (Polfa, Kutno, Poland) (density of 1.077 g / ml). After centrifugation at 1200×g for 20 min, the mononuclear cells from the interphase were harvested and washed 3 times with PBS. The cells were re-suspended in a standard culture medium consisting of RPMI-1640 medium,...
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