Synthesis of a Venetoclax-Lysozyme drug conjugate: a kidney regenerative therapy

Abstract

Introduction: The cells of our bodies can enter a senescent state in which they lose their ability to grow and divide but they do not enter apoptosis. The accumulation of senescent cells contributes to inflammation and age-related diseases. In the kidney, their accumulation causes kidney diseases. The elimination of senescent cells enhances regeneration and improve tissue functionality. Venetoclax is a BCL-2 inhibitor used in cancer but has also shown a good senolytic profile. Nonetheless, Venetoclax does not accumulate in kidney and its administration as senolytic agent would cause severe adverse reactions. Synthetising a drug conjugate to deliver Venetoclax to kidney can regenerate kidney functionality and minimize the risk of adverse reactions. Methods and results: We attempted to direct Venetoclax to kidneys using chicken egg white lysozyme bounded through Platinum linkage technology. Due to solubility incompatibilities, the lysozyme was replaced by PAMAMA G3 dendrimer. The identity and drug release capability were assessed through displacement reactions with KSCN. Conclusion: UPLC and displacement reactions indicate the conjugation of Venetoclax-Lx-Dendrimer was successful, further tests must be performed to confirm safety and efficacy of the conjugate in kidney cells. To account for possible accumulation problems, we suggest repeating the synthesis using a biodegradable dendrimer instead.