Thymogen

At a Glance

Classification: Synthetic dipeptide (L-glutamyl-L-tryptophan); Khavinson-school peptide bioregulator; immunomodulator registered in Russia

Thymogen is a two-amino-acid peptide, L-glutamic acid bonded to L-tryptophan (Glu-Trp, or "EW"). Soviet researchers in Leningrad (Morozov, Khavinson and colleagues) isolated it from Thymalin, the calf-thymus peptide extract, in the 1980s. They then made it synthetically and registered it in Russia as an immunomodulating medicine. It belongs to the same "peptide bioregulator" family as Thymalin, Vilon (Lys-Glu) and Epitalon. Thymogen is studied for: • Immune modulation, including T-cell differentiation and neutrophil function • Preventing acute respiratory infections • Aging and spontaneous tumor development in rodents • Protection against radiation-induced cancer in rodents • Mirror-image (D-amino acid) versions with opposite, immune-suppressing activity. Thymogen is not approved by the FDA or EMA. Most research comes from Russian groups linked to its developers. Under the name IM862, a Glu-Trp dipeptide was tested in the US against AIDS-related Kaposi's sarcoma; it failed in a phase III trial (see notes).

What Is Thymogen?

Thymogen is a defined synthetic dipeptide, unlike its parent extract Thymalin. Calf-thymus extract (Thymalin) ↓ chromatography isolates the L-Glu-L-Trp dipeptide ↓ it is synthesized chemically ↓ and registered as the medicine Thymogen. Its mirror-image relative, Thymodepressin (built from D-amino acids), was developed as an immune suppressor. The developers present the pair as an example of how a peptide's chirality can reverse its effect.

What Are Researchers Studying?

How Does It Work?

Proposed mechanisms (mostly from the developing groups): L-Glu-L-Trp ↓ reported to activate T-cell differentiation and T-cell recognition of antigens ↓ changes cyclic nucleotide (cAMP/cGMP) balance inside immune cells ↓ activates neutrophil movement (chemotaxis) and phagocytosis ↓ proposed "normalization" of immune function, rather than plain stimulation. Chirality matters: in mouse stem-cell experiments, versions containing L-glutamate had no effect on bone marrow precursor cells, some D-glutamate versions inhibited them, and one variant stimulated them. A specific receptor has not been identified. Small dipeptides like this are normally broken down quickly, and oral absorption is poor enough that chemists have tried modifying the molecule to improve it.

What Does the Research Show?

Notable Studies

What We Still Don't Know

• Whether Thymogen prevents infections or helps immune conditions in modern randomized, blinded trials • How a dipeptide this small, which is normally broken down quickly, produces lasting effects • Its molecular target or receptor • Whether the rodent aging and anti-tumor results replicate outside the originating groups • Human pharmacokinetics by nasal, injected or oral routes • Long-term safety data in English-language literature • Whether IM862's failure in Kaposi's sarcoma says anything about Thymogen's immune uses (different indication and endpoints). Human evidence is old, mostly Russian-language and largely uncontrolled.

Related Compounds

Sources & References

1. Anisimov VN, Khavinson VK, Morozov VG. Immunomodulatory synthetic dipeptide L-Glu-L-Trp slows down aging and inhibits spontaneous carcinogenesis in rats. Biogerontology. 2000;1(1):55–59.
2. Anisimov VN, Miretskiĭ GI, Morozov VG, et al. [The effect of the synthetic immunomodulator thymogen on radiation-induced carcinogenesis in rats]. Vopr Onkol. 1992;38(4):451–458. (Russian.)
3. Furgal SM, Degtiarev AA, Seryĭ SV, Khavinson VKh. [The clinico-epidemiological efficacy of thymogen in acute respiratory viral infections in a military collective]. Voen Med Zh. 1993;(2):31–32, 80. (Russian.)
4. Semina OV, Semenets TN, Zamulaeva IA, et al. Effects of structural and "mixed" isomers of Glu-Trp dipeptide on normal hemopoietic stem cells. Bull Exp Biol Med. 2006;141(2):250–253.
5. Bergeon JA, Chan YN, Charles BG, Toth I. Oral absorption enhancement of dipeptide L-Glu-L-Trp-OH by lipid and glycosyl conjugation. Biopolymers. 2008;90(5):633–643.
6. Deigin V, Linkova N, Vinogradova J, et al. The First Reciprocal Activities of Chiral Peptide Pharmaceuticals: Thymogen and Thymodepressin, as Examples. Int J Mol Sci. 2024;25(9):5042.
7. Tulpule A, Scadden DT, Espina BM, et al. Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposi's sarcoma. J Clin Oncol. 2000;18(4):716–723.
8. Noy A, Scadden DT, Lee J, et al. Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi's sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy. J Clin Oncol. 2005;23(5):990–998.