Modeling the Effects of Small Molecule Therapeutics on Glycolysis and Lactate Flux

Abstract

Chinese Hamster Ovary (CHO) cells are widely used in the industrial production of commercial therapeutics. One key aspect to the productivity of these cells is their high rate of glucose consumption. The high rate of glucose consumption is paired with a high output of lactate which can lead to negative culture performance. The rate of glucose consumption and lactate production can be modulated by a number of chemicals, some of which are being explored as therapeutic drugs, which affect the activities of the enzymes involved in glucose metabolism. This research aimed to evaluate the effects caused by small molecule therapeutics on CHO cells’ metabolism using a mathematic model of glucose metabolism. To model the therapeutics, established kinetic information for these therapeutics was implemented into a metabolic model. Then different concentrations of therapeutics were explored to assess their effects on metabolism. In addition, combinations of therapeutics were examined to study the effects of more drastic changes to metabolism. These therapeutics showed a large impact to the bistability of glucose metabolism as well as the lactate flux. These outcomes were important due to the potential to increase the productivity of CHO cells for industrial use as well as decreasing cell death. Thus, these therapeutics could be used to reduce lactate production in cells allowing for higher productivity.