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PubMed1975

Defective phagocytosis due to deficiencies involving the tetrapeptide tuftsin.

A description of the symptoms and causes of tuftsin deficiency is presented. Two major causes which give rise to a deficiency of the tetrapeptide (thr-lys-pro-arg) are discussed. One is familial tuftsin deficiency syndrome that results from an inherited mutation involving the tetrapeptide. All patients give a history of repeated infection with variable severity. One parent, father or mother, is deficient and occasionally other siblings may have the disease. The other type of deficiency is the result of loss of splenic function whether it is due to surgical removal of the spleen and to infarction or infiltration of the organ. A method for the assay of tuftsin activity is described.

Adolescent↗
PubMed2005

Tuftsin-bearing liposomes as antibiotic carriers in treatment of macrophage infections.

Tuftsin is a tetrapeptide (Thr-Lys-Pro-Arg) that specifically binds monocytes, macrophages, and polymorphonuclear leukocytes and potentiates their natural killer activity against tumors and pathogens. The antimicrobial activity of this peptide is significantly increased by attaching at the C-terminus a fatty acyl residue through the ethylenediamine spacer arm. This activity is further augmented by incorporating the modified tuftsin in the liposomes. The tuftsin-bearing liposomes not only enhance the host's resistance against a variety of infections but also serve as useful vehicles for the site-specific delivery of drugs in a variety of macrophage-based infections, such as tuberculosis and leishmaniasis.

Animals↗
PubMed1992

Quenched molecular dynamics simulations of tuftsin and proposed cyclic analogues.

We have used high-temperature quenched molecular dynamics calculations to investigate the conformational properties of tuftsin (Thr-Lys-Pro-Arg) in solution. Conformers obtained after quenching of the dynamical structures were sorted into families depending on their relative energies and backbone conformations. By examination of these families, several cyclic analogues of tuftsin were proposed and examined theoretically by further quenched dynamics simulations. Two of the four proposed analogues were found to adopt essentially identical conformations to that of linear tuftsin. It is suggested that these two derivatives (cyclo[Thr-Lys-Pro-Arg-Gly] and cyclo[Thr-Lys-Pro-Arg-Asp]) may be biologically active, and that the introduction of cyclic conformational constraints should help to reduce the entropic penalty to peptide binding.

Amino Acid Sequence↗
PubMed2003

Use of tuftsin bearing nystatin liposomes against an isolate of Candida albicans showing less in vivo susceptibility to amphotericin B.

In the present study, we evaluated tuftsin bearing nystatin liposomes for their potential against an isolate of Candida albicans (C. albicans) showing less in vivo susceptibility to amphotericin B (Amp B). The liposomised-Amp B in higher doses was found to be effective in elimination of less susceptible strain of C. albicans (C. albicans JMCR) in Balb/c mice, but may not be recommended due to toxicity constraints. On the other hand, liposomal nystatin was shown to possess higher efficacy as compared to that of Amp B, and was pertinent in treatment of C. albicans JMCR strain. The data of present work reveals that the incorporation of nystatin in tuftsin-bearing-liposomes results in a significant increase in its efficacy against experimental murine candidiasis. Interestingly, the pre-treatment of animals with liposomised-tuftsin prior to challenge with C. albicans infection was more effective in elimination of the pathogen from host and shows an advantage in prophylactic perspectives.

Adjuvants, Immunologic↗
PubMed2003

Immunomodulator tuftsin augments antifilarial activity of diethylcarbamazine against experimental brugian filariasis.

In the present study, we evaluated the potential of an immunomodulator tuftsin in increasing the efficacy of liposomised diethylcarbamazine (DEC) against experimental filarial infection of Brugia malayi. The liposomised form of DEC, when used at sub-optimal dose of 25 mg/kg body weight, successfully eliminated filarial parasite from systemic circulation in animals inflicted with B. malayi infection. However, the formulation was effective upto 60 days post infection only, followed by recurrence of the infection. In contrast, the co-administration of liposomal formulation of DEC along with an immunomodulator tuftsin was found to be competent enough to suppress microfilarial stage of parasite till 90 days post treatment. Interestingly, tuftsin bearing DEC liposomes were found to be effective against adult parasite as well.

Adjuvants, Immunologic↗
PubMed1987

Synthesis of modified tuftsins containing monosaccharides or monosaccharide derivatives.

Synthesis of some modified tuftsins is described in which a monosaccharide or a monosaccharide derivative was incorporated in the molecule. Acylation of H-Thr-Lys(Z)-Pro-Arg(NO2)-OBzl with D(+)-gluco-1,5-lactone followed by catalytic hydrogenation gave N alpha-gluconyl-tuftsin. Glycosylation of the carboxyl function of the C-terminal arginine has been achieved by reacting, through the mixed anhydride procedure, Boc-Thr-Lys(Z)-Pro-OH with 2-deoxy-2-(NG-nitroargininamido)-D-glucopyranose followed by catalytic hydrogenation and trifluoroacetic acid treatment. O-Glucosyl-tuftsin has been prepared by reacting o-nitrophenyl N-benzyloxycarbonyl-O-[(alpha + beta) 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl]-threoninate with H-Lys(Z)-Pro-Arg(NO2)-OBzl in the presence of 1-hydroxybenzotriazole. Flash chromatography on silica gel allowed a partial separation of the diastereoisomers, one of which has been isolated in a reasonable yield. The single diastereoisomer and the alpha + beta anomeric mixture were separately deblocked by catalytic hydrogenation and purified by RP-HPLC.

Carbohydrates↗
PubMed1990

Competition between tuftsin and HBV S-protein sequences.

The syntheses of HBV S-protein partial sequences: Thr-Lys-Pro-Thr (I), Thr-Lys-Pro-Thr-Asp (II), and Thr-Lys-Pro-Thr-Asp-Gly (III) and also of pentapeptide Thr-Lys-Pro-Gly-Arg (IV), are described. For the peptides II and III inhibitory activity against tuftsin was found. Peptide IV (an analogue of tuftsin-inhibitor Thr-Lys-Pro-Pro-Arg) demonstrated a tuftsin-like activity in the phagocytosis experiments.

Amino Acid Sequence↗
PubMed1990

Synthesis of O-glycosylated tuftsins by utilizing threonine derivatives containing an unprotected monosaccharide moiety.

Synthesis is described of four tuftsin derivatives containing a D-glucopyranosyl or a D-galactopyranosyl unit covalently linked to the hydroxy side chain function of the threonine residue through either an alpha or beta O-glycosidic linkage. Fmoc-threonine derivatives containing the suitable unprotected sugar were used for incorporating the O-glycosylated amino acid residue. Z-Thr[alpha-Glc(OBzl)4]-OBzl and Z-Thr[alpha-Gal(OBzl)4]-OBzl were prepared from the tetra-O-benzylated sugar and Z-Thr-OBzl by the trichloroacetimidate method in the presence of trimethylsilyl trifluoromethane sulfonate. The alpha glycosylated threonine derivatives were converted into Fmoc-Thr(alpha-Glc)-OH and Fmoc-Thr(alpha-Gal)-OH by catalytic hydrogenation followed by acylation with Fmoc-OSu. beta-Glucosylation and beta-galactosylation of threonine were carried out by reacting the proper per-O-acetylated sugar with Z-Thr-OBzl and boron trifluoride ethyl etherate in dichloromethane. Catalytic hydrogenation of the beta-O-glycosylated threonine derivatives followed by acylation with Fmoc-OSu and deacetylation with methanolic hydrazine yielded Fmoc-Thr(beta-Glc)-OH and Fmoc-Thr(beta-Gal)-OH, respectively. The O-glycosylated threonine derivatives were then reacted with H-Lys(Z)-Pro-Arg(NO2)-OBzl in the presence of DCC and HOBt and the resulting glycosylated tuftsin derivatives were fully deblocked by catalytic hydrogenation, purified by HPLC, and characterized by optical rotation, amino acid analysis, and 1H NMR. The beta-galactosylated tuftsin was also prepared by the continuous flow solid phase procedure.

Amino Acid Sequence↗
PubMed1993

Synthesis and biological activity of [L-hydroxyproline]3-tuftsin analogue and its alpha- or beta-O-D-glucosylated derivatives.

Syntheses are described of the Hyp3-tuftsin analogue and of its derivatives alpha- or beta-O-glycosylated at the side chain function of the hydroxyproline residue. The carbohydrate-free tetrapeptide was prepared by reacting Z-Thr-Lys(Z)-OH with H-Hyp-Arg(NO2)-OBzl by the mixed anhydride procedure. In the synthesis of the alpha-glycosylated analogue the O-glycosyl amino acid was incorporated by reacting Boc-(Glc alpha+beta)Hyp-OH with H-Arg(NO2)-OBzl through the same procedure. The alpha-glucosylated dipeptide was isolated from the diastereomeric mixture, selectively deblocked, and acylated with Z-Thr-Lys(Z)-OH by the mixed anhydride procedure. In the preparation of the beta-glucosylated analogue the BOP procedure was used for reacting Boc-[Glc(Ac)4 beta]Hyp-OH with H-Arg(NO)2-OBzl was well as for the final coupling to tetrapeptide. Removal of protecting groups from crude tetrapeptides was achieved by catalytic hydrogenation. Deacetylation of the sugar moiety of the beta-glucosylated tetrapeptide was achieved by treatment with sodium methoxide in methanol. The synthetic compounds were isolated by ion exchange chromatography, and characterized by elemental analysis, amino acid analysis, optical rotation and proton NMR. Their capacity to evoke the release of interleukin 1 from mouse peritoneal macrophages and to modulate immunogenic activity of antigen-fed cells was evaluated, in comparison with tuftsin and rigin. All of the analogues were found to possess tuftsin-like activity.

Amino Acid Sequence↗
PubMed1995

Synthesis and immunological evaluation of the conjugates composed from a muramyl peptide GMDP and tuftsin.

The conjugates of a muramyl dipeptide analog GMDP (N-acetylglucosaminyl beta 1-->4 N-acetylmuramyl-L-alanyl-D-isoglutamine) and tuftsin (Thr-Lys-Pro-Arg) were synthesized from unprotected GMDP by mixed anhydride procedure. The identity of the conjugates was confirmed by high resolution NMR and their immunomodulating properties were determined in various tests. It was found that the conjugate in which the GMDP carboxyl group forms an amide bond with the epsilon-amino group of tuftsin lysyl residue exceeds GMDP in all the activities determined. Synergism of GMDP and tuftsin was found in phagocytosis stimulation assay.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Prophylactic use of liposomized tuftsin enhances the susceptibility of Candida albicans to fluconazole in leukopenic mice.

In the present study, we investigated the immunopotentiating activity of the immunomodulator tuftsin for the treatment of dose-dependent susceptible Candida albicans infection in a murine model. Our results demonstrated that tuftsin increases the susceptibility of C. albicans to phagocytosis by activating murine macrophages. Fluconazole used for the treatment of mice infected with C. albicans showed less in vivo efficacy and proved to be ineffective in the elimination of the infection from leukopenic mice even at higher doses. However, the antifungal activity of fluconazole against the same isolate of C. albicans significantly increased in tuftsin-pretreated mice and resulted in an improved survival rate in mice. The treated mice also showed less severity of infection as supported by a reduced fungal burden in their kidneys. This study indicates that the use of immunopotentiating substances can enhance the therapeutic efficacy of azole antifungal agents and thus can effectively combat azole-resistant fungal pathogens under conditions of immunosuppression.

Animals↗
PubMed1983

Tuftsin, a natural activator of phagocyte cells: an overview.

The recognition that a small oligopeptide was responsible for the full stimulation effect of specific cytophilic gamma-globulin on blood neutrophils arose from a study of the kinetics of phagocytosis. These were unusual in that the stimulation was short lived and that preincubation of the phagocyte with the gamma-globulin rendered the latter inactive. The oligopeptide was isolated, its structure determined (Thr-Lys-Pro-Arg) and synthesized. The discovery of human mutants with tuftsin deficiency exhibiting signs and symptoms of frequent severe infection further emphasized the specific biological function of the tetrapeptide. The mutant peptide was isolated, sequenced (Thr-Glu-Pro-Arg), and synthesized. Further studies showed that tuftsin requires two enzymes for its liberation from the parent carrier gamma-globulin. One enzyme is in the spleen that cleaves distal to the arginine end, and the other, on the outer side of the plasma membrane, cleaves proximal to the threonine residue. The tetrapeptide tuftsin stimulates all functions of phagocytic cells: phagocytosis, pinocytosis, motility, immunogenic activity including processing of the antigen and augmentation of the number of antibody-forming cells, bactericidal activity, and, above all, tumoricidal activity. The latter has been shown by several laboratories.

Amino Acid Sequence↗
PubMed1980

Decreased serum tuftsin concentrations in sickle cell disease.

The serum concentrations of the phagocytosis-stimulating peptide, tuftsin, were determined by radioimmunoassay in 21 patients with sickle cell disease and in 12 healthy controls. The mean serum tuftsin concentration was significantly lower in patient with haemoglobin SS disease (154.3 +/- 35.1 ng/ml; 308.6 +/- 70.2 nmol/l, P < 0.01) and in patients with haemoglobin SC and CC disease (180.9 +/- 42.7 ng/ml; 361.8 +/- 85.4 nmol/l, P < 0.05) than in healthy controls (228.7 +/- 46.7 ng/ml; 457.4 +/- 93.4 nmol/1). Tuftsin deficiency is an indicator of splenic hypofunction and may contribute to the increased susceptibility of patients with sickle cell disease to severe infection.

Adolescent↗
PubMedDate not supplied

Effect of tuftsin on the phagocytotic activity of the unicellular Tetrahymena. Does primary interaction develop imprinting?

The natural mammalian phagocytosis stimulator tetrapeptide tuftsin stimulated also the phagocytosis of the unicellular Tetrahymena. The selectivity of the Tetrahymena was not complete, as threonin-free tuftsin provoked a greater response. Treatment with tuftsin did not develop functional imprinting, however the binding capacity of cell membrane significantly increased after the first treatment.

Animals↗
PubMed1992

Anti-inflammatory effect of tuftsin and its retro-inverso analogue in rat adjuvant arthritis.

Tuftsin, an immunostimulating tetrapeptide derived from immunoglobulin heavy chain, and its retro-inverso analogue have been tested in rat adjuvant arthritis. The secondary lesion of rats injected with Freund's adjuvant was significantly inhibited by both the natural and retro-inverso tuftsin administered orally. The retro-inverso analogue was at least tenfold more potent than the parent molecule, suggesting an increased stability to degradation, because of its molecular modification. The anti-inflammatory effect of tuftsin may be due to its ability to modulate macrophage function.

Animals↗
PubMedDate not supplied

Antinociceptive action of the SP1-4 tetrapeptide and of some tuftsin analogs.

The N-terminal tetrapeptide of substance P (SP1-4) was found to produce analgesia, after the icv injection to the rat brain, which is lower in its intensity than that produced by tuftsin (Thr-Lys-Pro-Arg tetrapeptide). Among investigated tuftsin analogues Thr-Lys-Pro-Thr and Thr-Lys-Pro-Thr-Asp (partial sequences of S-protein of HB virus) were weakly active, Thr-Arg-Pro-Arg was inactive, and Thr-Lys-Pro-Gly-Arg produced a weak hyperalgesia 30 min after the icv injection. The obtained results were compared with those obtained previously in the phagocytosis stimulation test. In the control experiments the effects of free amino acids of the tuftsin molecule (Thr, Lys, Pro, Arg) were also studied.

Analgesia↗
PubMed1991

[Use of tuftsin in experimental leprosy].

The effect of tuftsin was studied in vivo using CBA mice infected with M. leprae by Shepard's technique and in vitro using macrophage-like cell line P. 388 (Co-cultivated with M. leprae) and the cultivated leproma tissue. It was found out that tuftsin acted as a stimulator of M. leprae multiplication in foot-pads of mice and as a prolongator of M. leprae survival in the cells of macrophage-like cell line P .388. It is concluded that using tuftsin might be useful in view of studying different aspects of experimental leprosy.

Animals↗
PubMed1991

Effect of intraperitoneal tuftsin administration on histamine concentration in tissues of guinea-pigs.

The performed studies dealt with the effect of tuftsin (tetrapeptide Thr-Lys-Pro-Arg), a stimulator of many components of immunological reactions, exerted on histamine concentration in lungs, kidneys, liver, duodenal wall and arterial blood of guinea-pigs. Tuftsin was given intraperitoneally, in a single dose (0.5 and 1.0 mg/kg) or three times at one-hour intervals (1.0 mg/kg). It has been revealed that tuftsin alters the histamine concentration in tissues of guinea-pigs by lowering it in lungs, and by elevating it in kidneys and liver, in the latter insignificantly.

Amino Acid Sequence↗