Psychotropic drugs interaction with the lipid nanoparticle of COVID-19 mRNA therapeutics

Abstract

The messenger RNA (mRNA) vaccines for COVID-19, Pfizer-BioNTech and Moderna, were authorized in the US on an emergency basis in December of 2020. The rapid distribution of these therapeutics around the country and the world led to millions of people being vaccinated in a short time span, an action that decreased hospitalization and death but also heightened the concerns about adverse effects and drug-vaccine interactions. The COVID-19 mRNA vaccines are of particular interest as they form the vanguard of a range of other mRNA therapeutics that are currently in the development pipeline, focusing both on infectious diseases as well as oncological applications. The Vaccine Adverse Event Reporting System (VAERS) has gained additional attention during the COVID-19 pandemic, specifically regarding the rollout of mRNA therapeutics. However, for VAERS, absence of a reporting platform for drug-vaccine interactions left these events poorly defined. For example, chemotherapy, anticonvulsants, and antimalarials were documented to interfere with the mRNA vaccines, but much less is known about the other drugs that could interact with these therapeutics, causing adverse events or decreased efficacy. In addition, SARS-CoV-2 exploitation of host cytochrome P450 enzymes, reported in COVID-19 critical illness, highlights viral interference with drug metabolism. For example, patients with severe psychiatric illness (SPI) in treatment with clozapine often displayed elevated drug levels, emphasizing drug-vaccine interaction.

Keywords: DSPC; LNP; PEGylated lipids; cell-cell fusion; cholesterol analogs; ionizable lipids; psychotropic drugs.

FIGURE 1

LNPs enter host cells via endocytosis or phagocytosis (immune cell endocytosis). LNP is trafficked through the ELS, traveling from early to late endosomes. Progressing from late endosome to lysosomes would risk LNP degradation by the hydrolyzing enzymes; therefore, ELS escape must take place in late endosome. However, late endosomes may expulse their cargo into the extracellular compartment via EVs (not shown). This is a major hurdle that LNPs must negotiate. Under ideal circumstances, ribosomes translate the exogenous mRNA into the S protein. For this to occur, it must be assumed that the human translation machinery does not differentiate between endogenous (nucleus-derived) and exogenous mRNA.