Evaluation of therapeutic strategies targeting BCAA catabolism using a systems pharmacology model

Veronika Voronova; Victor Sokolov; Yannick Morias; Malin Jonsson Boezelman; Maria Wågberg; Marcus Henricsson; Karl Hansson; Alexey Goltsov; Kirill Peskov; Monika Sundqvist

doi:10.3389/fphar.2022.993422

Evaluation of therapeutic strategies targeting BCAA catabolism using a systems pharmacology model

Front Pharmacol. 2022 Nov 28:13:993422. doi: 10.3389/fphar.2022.993422. eCollection 2022.

Authors

Veronika Voronova¹, Victor Sokolov^{1

2}, Yannick Morias³, Malin Jonsson Boezelman³, Maria Wågberg³, Marcus Henricsson⁴, Karl Hansson⁵, Alexey Goltsov^{1

6}, Kirill Peskov^{1

2

7}, Monika Sundqvist⁵

Affiliations

¹ M&S Decisions LLC, Moscow, Russia.
² STU Sirius, Sochi, Russia.
³ Bioscience Cardiovascular, Research and Early Development, Cardiovascular Renal and Metabolism (CVRM), BioPharmaceutical R&D AstraZeneca, Gothenburg, Sweden.
⁴ Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular Renal and Metabolism (CVRM), BioPharmaceutical R&D AstraZeneca, Gothenburg, Sweden.
⁵ Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular Renal and Metabolism (CVRM), BioPharmaceutical R&D AstraZeneca, Gothenburg, Sweden.
⁶ Institute for Artificial Intelligence, Russian Technological University (MIREA), Moscow, Russia.
⁷ I.M. Sechenov First Moscow State Medical University, Moscow, Russia.

Abstract

Background: Abnormal branched-chained amino acids (BCAA) accumulation in cardiomyocytes is associated with cardiac remodeling in heart failure. Administration of branched-chain α-keto acid dehydrogenase (BCKD) kinase inhibitor BT2 has been shown to reduce cardiac BCAA levels and demonstrated positive effects on cardiac function in a preclinical setting. The current study is focused on evaluating the impact of BT2 on the systemic and cardiac levels of BCAA and their metabolites as well as activities of BCAA catabolic enzymes using a quantitative systems pharmacology model. Methods: The model is composed of an ordinary differential equation system characterizing BCAA consumption with food, disposal in the proteins, reversible branched-chain-amino-acid aminotransferase (BCAT)-mediated transamination to branched-chain keto-acids (BCKA), followed by BCKD-mediated oxidation. Activity of BCKD is regulated by the balance of BCKDK and protein phosphatase 2Cm (PP2Cm) activities, affected by BT2 treatment. Cardiac BCAA levels are assumed to directly affect left ventricular ejection fraction (LVEF). Biochemical characteristics of the enzymes are taken from the public domains, while plasma and cardiac BCAA and BCKA levels in BT2 treated mice are used to inform the model parameters. Results: The model provides adequate reproduction of the experimental data and predicts synchronous BCAA responses in the systemic and cardiac space, dictated by rapid BCAA equilibration between the tissues. The model-based simulations indicate maximum possible effect of BT2 treatment on BCAA reduction to be 40% corresponding to 12% increase in LVEF. Model sensitivity analysis demonstrates strong impact of BCKDK and PP2Cm activities as well as total BCKD and co-substrate levels (glutamate, ketoglutarate and ATP) on BCAA and BCKA levels. Conclusion: Model based simulations confirms using of plasma measurements as a marker of cardiac BCAA changes under BCKDK inhibition. The proposed model can be used for optimization of preclinical study design for novel compounds targeting BCAA catabolism.

Keywords: BCAA; BCKA; BCKDK; BT2; Model; cardiac hypertrophy; quantitative systems pharmacology.