ABSTRACT
Paxlovid, a drug combining nirmatrelvir and ritonavir, was designed for the treatment of COVID-19 and its rapid development has led to emergency use approval by the FDA to reduce the impact of COVID-19 infection on patients.In order to overcome potentially suboptimal therapeutic exposures, nirmatrelvir is dosed in combination with ritonavir to boost the pharmacokinetics of the active product.Here we consider examples of drugs co-administered with pharmacoenhancers.Pharmacoenhancers have been adopted for multiple purposes such as ensuring therapeutic exposure of the active product, reducing formation of toxic metabolites, changing the route of administration, and increasing the cost-effectiveness of a therapy.We weigh the benefits and risks of this approach, examining the impact of technology developments on drug design and how enhanced integration between cross-discipline teams can improve the outcome of drug discovery.
Subject(s)
COVID-19 , Drug Discovery , Ritonavir , Humans , Drug Industry , Myotonin-Protein KinaseABSTRACT
An intact lung epithelial barrier is essential for lung homeostasis. The Na+, K+-ATPase (NKA), primarily serving as an ion transporter, also regulates epithelial barrier function via modulation of tight junctions. However, the underlying mechanism is not well understood. Here, we show that overexpression of the NKA ß1 subunit upregulates the expression of tight junction proteins, leading to increased alveolar epithelial barrier function by an ion transport-independent mechanism. Using IP and mass spectrometry, we identified a number of unknown protein interactions of the ß1 subunit, including a top candidate, myotonic dystrophy kinase-related cdc42-binding kinase α (MRCKα), which is a protein kinase known to regulate peripheral actin formation. Using a doxycycline-inducible gene expression system, we demonstrated that MRCKα and its downstream activation of myosin light chain is required for the regulation of alveolar barrier function by the NKA ß1 subunit. Importantly, MRCKα is expressed in both human airways and alveoli and has reduced expression in patients with acute respiratory distress syndrome (ARDS), a lung illness that can be caused by multiple direct and indirect insults, including the infection of influenza virus and SARS-CoV-2. Our results have elucidated a potentially novel mechanism by which NKA regulates epithelial tight junctions and have identified potential drug targets for treating ARDS and other pulmonary diseases that are caused by barrier dysfunction.