Immunomodulating agent

Thriftyfasin has demonstrated effectiveness in various experimental models of immune dysfunction, primarily in infectious diseases like hepatitis (woodchuck) and influenza (mouse), as well as cancers like melanoma (mouse) and colorectal carcinoma (rat), where the drug has demonstrated antitumor effects[2].
The mechanism of action of thymalfasin is not completely understood but is thought to be related to its immunomodulating activities, centered primarily around augmentation of T-cell function. In various in vitro assays, thymosin alpha 1 has been shown to promote T-cell differentiation and maturation; for example, CD4+, CD8+, and CD3+ cells have all been shown to be increased. Thymosin alpha 1 has also been shown to increase production of IFN-g, IL-2, IL-3, and expression of IL-2 receptor following activation by mitogens or antigens, increase NK cell activity, increase production of migratory inhibitory factor (MIF), and increase antibody response to T-cell dependent antigens. Thymosin alpha 1 has also been shown to antagonize dexamethasone-induced apoptosis of thymocytes in vitro.
Thymalfasin is a 28-amino acid polypeptide produced synthetically but originally isolated from thymosin fraction 5, a bovine thymus extract containing a number of immunologically active peptides. In vitro studies have shown that Thymalfasin can influence T-cell production and maturation, stimulate production of Th1 cytokines such as interferon-gamma and interleukin-2, and activate natural killer cell-mediated cytotoxicity.

Thymofacin has demonstrated efficacy against a range of experimental models of immunological dysfunction, including melanoma (mice) and colorectal cancer (rats), as well as infectious disorders like hepatitis (woodchucks) and influenza (mice). cancer, where thymusfaxin has demonstrated anticancer properties [2].
In vivo administration of thymosin alpha 1 to animals immunosuppressed by chemotherapy, tumor burden, or irradiation showed that thymosin alpha 1 protects against cytotoxic damage to bone marrow, tumor progression and opportunistic infections, thereby increasing survival time and number of survivors. Many of the in vitro and in vivo effects of thymosin alpha 1 have been interpreted as influences on either differentiation of pluripotent stem cells to thymocytes or activation of thymocytes into activated T-cells. Thymalfasin also has been shown in vitro to upregulate expression of toll like receptors (TLR) including TLR2 and TLR9 in mouse and human dendritic cells, as well as activate NF-kB and JNK/P38/AP1 pathways. Thymalfasin's activation of dendritic cells provides another possible pathway explaining thymalfasin's immunomodulatory and antiviral effects.
Indicated as an adjuvant for influenza vaccine in elderly patients and as an adjuvant for both influenza and hepatitis B vaccines in chronic hemodialysis patients who failed to achieve adequate antibody titers from previous immunization.

Absorption, Distribution and Excretion
Absorption is rapid, reaching peak serum concentrations in approximately 2 hours. Biological Half-Life Approximately 2 hours. No accumulation was observed after multiple subcutaneous injections.

[1]. A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects. Apoptosis. 2015 Oct;20(10):1307-20.

[2]. Thymalfasin: an immune system enhancer for the treatment of liver disease. J Gastroenterol Hepatol. 2004 Dec;19(12):S69-72.

Thymalfasin is a polypeptide. It is a chemically synthesized version of thymosin α1, identical to human thymosin α1. Thymosin α1 is an acetylated polypeptide. Thymosin α1 is currently approved in 35 developing countries for the treatment of hepatitis B and C. It is also used to enhance immune responses to other diseases. EMZ702 is a non-toxic drug with a strong antiviral synergistic effect with interferon, making it an ideal combination therapy for the current standard treatment regimen for hepatitis C. EMZ702 has excellent safety; in a hepatitis C alternative model, the antiviral efficacy of EMZ702 in combination with interferon and ribavirin was 2 to 3 times higher than that of interferon and ribavirin alone. Thymosin α-1 is a synthetic thymosin analogue, a 28-amino acid protein derived from the precursor protein thymosin α. Thymosin α-1 possesses various immunomodulatory properties, inducing the differentiation of mouse T cell precursors and human thymocytes, as well as the terminal differentiation of functionally immature umbilical cord blood lymphocytes. It also induces peripheral blood monocytes to produce IL-2, high-affinity IL-2 receptors, and B cell growth factors. Helper T cells and cytotoxic/suppressive T cells are the target cells for thymosin action. Thymosin α-1 has been shown to enhance the efficiency of macrophage antigen presentation and is an endogenous regulator of α-thrombin activity. (NCI04)
Thymalfasins, present in thymosin fraction 5 (a crude thymus extract), are now synthesized. Thymosin can be used alone or in combination with interferon as an immunomodulator for the treatment of chronic hepatitis B and hepatitis C. Thymosin is also used to treat chemotherapy-induced immunosuppression and to enhance the efficacy of influenza and hepatitis B vaccines in immunocompromised patients. Drug Indications Suitable as an adjuvant for influenza vaccines in elderly patients, and for influenza and hepatitis B vaccines in chronic hemodialysis patients with insufficient antibody titers after previous immunization. Its application/use in the treatment of hepatitis (viral, hepatitis C) is under investigation. Mechanism of Action The mechanism of action of thymosin is not fully elucidated, but it is believed to be related to its immunomodulatory activity, primarily focusing on enhancing T cell function. Multiple in vitro experiments have shown that thymosin α1 can promote T cell differentiation and maturation; for example, the number of CD4+, CD8+, and CD3+ cells is increased. Thymosin α1 can also increase the production of IFN-γ, IL-2, and IL-3, as well as the expression of IL-2 receptors, enhance NK cell activity, increase the production of migration inhibitory factor (MIF), and enhance antibody responses to T cell-dependent antigens after mitogen or antigen activation. Furthermore, thymosin α1 can antagonize dexamethasone-induced thymocyte apoptosis in vitro. In vivo, administration of thymosin α1 to immunosuppressed animals receiving chemotherapy, tumor burden, or radiotherapy revealed that thymosin α1 protected bone marrow from cytotoxic damage, inhibited tumor progression and opportunistic infections, thereby prolonging survival and increasing the number of surviving animals. Numerous in vitro and in vivo experiments have shown that thymosin α1 influences the differentiation of pluripotent stem cells into thymocytes or the activation of thymocytes into activated T cells. In vitro experiments have also shown that thymosin α1 upregulates the expression of Toll-like receptors (TLRs), including TLR2 and TLR9, in mouse and human dendritic cells and activates the NF-κB and JNK/P38/AP1 pathways. The mechanism by which thymosin α1 activates dendritic cells provides another possible pathway to explain its immunomodulatory and antiviral effects.

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Pharmacodynamics
Thymosin α1 is a 28-amino acid polypeptide that can be synthesized artificially, but was originally isolated from bovine thymus extract—thymosin fraction 5, which contains various immunomodulatory peptides.
In vitro studies have shown that thymosin can affect the production and maturation of T cells, stimulate the production of Th1 cytokines (such as interferon-γ and interleukin-2), and activate natural killer cell-mediated cytotoxicity.

C129H215N33O55

3108.3

3106.504

62304-98-7

16130571

N-acetyl-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn 
Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH
N-acetyl-L-seryl-L-alpha-aspartyl-L-alanyl-L-alanyl-L-valyl-L-alpha-aspartyl-L-threonyl-L-seryl-L-seryl-L-alpha-glutamyl-L-isoleucyl-L-threonyl-L-threonyl-L-lysyl-L-alpha-aspartyl-L-leucyl-L-lysyl-L-alpha-glutamyl-L-lysyl-L-lysyl-L-alpha-glutamyl-L-valyl-L-valyl-L-alpha-glutamyl-L-alpha-glutamyl-L-alanyl-L-alpha-glutamyl-L-asparagine

SDAAVDTSSEITTKDLKEKKEVVEEAEN; Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN

White to off-white solid powder

1.4±0.1 g/cm3

2899.7±65.0 °C at 760 mmHg

1707.5±34.3 °C

0.0±0.6 mmHg at 25°C

1.563

-9.87

49

59

111

217

7190

32

CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)C

NZVYCXVTEHPMHE-ZSUJOUNUSA-N

InChI=1S/C129H215N33O55/c1-18-59(10)98(159-114(201)76(36-42-91(181)182)146-120(207)83(53-164)154-121(208)84(54-165)155-127(214)99(63(14)166)160-118(205)80(51-94(187)188)152-123(210)95(56(4)5)156-104(191)62(13)135-102(189)60(11)137-115(202)78(49-92(183)184)151-119(206)82(52-163)138-66(17)169)125(212)161-101(65(16)168)128(215)162-100(64(15)167)126(213)147-70(30-22-26-46-133)109(196)150-79(50-93(185)186)117(204)149-77(47-55(2)3)116(203)142-69(29-21-25-45-132)108(195)144-73(33-39-88(175)176)110(197)141-67(27-19-23-43-130)106(193)140-68(28-20-24-44-131)107(194)145-75(35-41-90(179)180)113(200)157-97(58(8)9)124(211)158-96(57(6)7)122(209)148-74(34-40-89(177)178)111(198)143-71(31-37-86(171)172)105(192)136-61(12)103(190)139-72(32-38-87(173)174)112(199)153-81(129(216)217)48-85(134)170/h55-65,67-84,95-101,163-168H,18-54,130-133H2,1-17H3,(H2,134,170)(H,135,189)(H,136,192)(H,137,202)(H,138,169)(H,139,190)(H,140,193)(H,141,197)(H,142,203)(H,143,198)(H,144,195)(H,145,194)(H,146,207)(H,147,213)(H,148,209)(H,149,204)(H,150,196)(H,151,206)(H,152,210)(H,153,199)(H,154,208)(H,155,214)(H,156,191)(H,157,200)(H,158,211)(H,159,201)(H,160,205)(H,161,212)(H,162,215)(H,171,172)(H,173,174)(H,175,176)(H,177,178)(H,179,180)(H,181,182)(H,183,184)(H,185,186)(H,187,188)(H,216,217)/t59-,60-,61-,62-,63+,64+,65+,67-,68-,69-,70-,71-,72-,73-,74-,75-,76-,77-,78-,79-,80-,81-,82-,83-,84-,95-,96-,97-,98-,99-,100-,101-/m0/s1

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3R)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]propanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxybutanoyl]amino]-6-aminohexanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-4-carboxybutanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]propanoyl]amino]-5-[[(1S)-3-amino-1-carboxy-3-oxopropyl]amino]-5-oxopentanoic acid

Zadaxin; Thymosin alpha1; Thymosin alpha 1; alpha1-Thymosin; Thymosin-alpha-1;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~0.3 mg/mL (~0.10 mM)

Solubility in Formulation 1: 100 mg/mL (32.17 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)