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Proteolytic Hydrolysis of the Antitumor Peptide HLDF-6-AA in Blood Plasma

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Abstract

HLDF-6 hexapeptide, which corresponds to the 41TGENHR46 fragment of human leukemia differentiation factor (HLDF), shows a wide range of neuroprotective, normalizing, anxiolytic, nootropic and antitumor activities. A promising drug with antitumor activity is being developed based on the N-acetyl, C‑amide form of HLDF-6 peptide, obtained by the solid phase method. Proteolytic hydrolysis of HLDF-6-AA peptide in blood plasma was studied using its derivatives labeled with hydrogen isotopes. The HLDF-6-AA peptide samples uniformly labeled with tritium and deuterium were obtained by the reaction of high-temperature solid-state catalytic isotope exchange at 170°С. [3H] HLDF-6-AA peptide was obtained with the molar radioactivity of 50 Ci/mmol and the average deuterium incorporation for [2H] HLDF-6-AA peptide was 2.90 atoms per peptide molecule. Proteolytic hydrolysis of HLDF-6-AA peptide in rat blood plasma was studied using radiochromatography. It was established that the main pathway of its proteolytic hydrolysis in rat blood plasma consists in cleavage of His-Arg-NH2 (HR-NH2) dipeptide from the C-end of the amide with the half-degradation period of 35 min.

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Funding

This work was supported by the Ministry of Education and Science of the Russian Federation, state contract No 14.N08.11.0111 (“Preclinical studies of a peptide drug with antitumor, antimetastatic and protective action”) and the Basic Research Program of the Presidium of the Russian Academy of Sciences “Structural and functional research of endogenous peptides is the basis for the development of new pharmacologically important drugs” state registration number 01201353020.

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Authors and Affiliations

  1. Institute of Molecular Genetics, Russian Academy of Sciences, 123182, Moscow, Russia

    Yu. A. Zolotarev, A. K. Dadayan, V. S. Kozik, S. I. Shram, I. Yu. Nagaev & N. F. Myasoedov

  2. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Pushchino Branch, Russian Academy of Sciences, Pushchino, Moscow oblast, Russia

    V. N. Azev

  3. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia

    A. P. Bogachouk & V. M. Lipkin

Authors
  1. Yu. A. Zolotarev
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  2. A. K. Dadayan
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  3. V. S. Kozik
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  4. S. I. Shram
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  5. I. Yu. Nagaev
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  6. V. N. Azev
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  7. A. P. Bogachouk
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  8. V. M. Lipkin
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  9. N. F. Myasoedov
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Correspondence to Yu. A. Zolotarev.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Translated by D. Novikova

Abbreviations: HS, hydrogen spillover; HSCIE, high-temperature solid-state catalytic isotope exchange; HFBA, hexafluorobutyric acid; HLDF, human leukocyte differentiation factor; HLDF-6-AA (Ac-TGENHR-NH2), acetyl-amide form of HLDF-6 peptide.

Corresponding author: phone: +7 (499) 196-02-13; fax: +7 (499) 196-02-21; e-mail: zolya@img.ras.ru.

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Zolotarev, Y.A., Dadayan, A.K., Kozik, V.S. et al. Proteolytic Hydrolysis of the Antitumor Peptide HLDF-6-AA in Blood Plasma. Russ J Bioorg Chem 45, 347–352 (2019). https://doi.org/10.1134/S1068162019050133

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