Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

Repurposing drugs as treatments for COVID-19 has drawn much attention. Beginning with sigma receptor ligands, and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs, and does not reflect specific target-based activities, rather it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.

Cubosomes as Potential Nanocarrier for Drug Delivery: A Comprehensive Review

Lyotropic liquid crystalline cores are characterized as soft nanoparticles and referred as cubosomes. They are prepared to activate the natural self-assembly capability of lipids (e.g., monoolein or phytantriol) in water. Cubosomes are crystalline isotropic lipidic nanoparticles stabilized by Poloxamers such as F127, F108. It is made up of a network of two separate aqueous channels formed by a three-dimensional, non-intersecting lipid bilayer imposed over an indefinite periodic minimum surface of cubic symmetry. Cubosomes constitute unique features such as their special cubic structure which permits to incorporate highly lipophilic, hydrophilic, and amphiphilic drugs. Also, the lipids excipients used in the preparation of cubosomes such as monoolein, phytantriol are biodegradable and biocompatible so these cubic nanoparticles are referred as safe carrier for drug delivery. Cubic lipid nanoparticles have a highly stable cubic shape that allows for a slower rate of dissociation, improved drug retention, and site-specific drug delivery. The architecture of cubic particles provides suitability in the drug delivery as compared to other lipids-based drug delivery systems such as solid lipid nanoparticles (SLN), liposomes due to their drug expulsion to the surface of nanoparticles. Cubosomes with these loaded features/architectural composition led to an array of desired performance. Solvent evaporation, ultrasonication, hydrotrope, spray drying, melt dispersion emulsifying methods are used to prepare these carrier systems.

Phospholipidosis is a shared mechanism underlying the in vitro antiviral activity of many repurposed drugs against SARS-CoV-2

Repurposing drugs as treatments for COVID-19 has drawn much attention. A common strategy has been to screen for established drugs, typically developed for other indications, that are antiviral in cells or organisms. Intriguingly, most of the drugs that have emerged from these campaigns, though diverse in structure, share a common physical property: cationic amphiphilicity. Provoked by the similarity of these repurposed drugs to those inducing phospholipidosis, a well-known drug side effect, we investigated phospholipidosis as a mechanism for antiviral activity. We tested 23 cationic amphiphilic drugs—including those from phenotypic screens and others that we ourselves had found—for induction of phospholipidosis in cell culture. We found that most of the repurposed drugs, which included hydroxychloroquine, azithromycin, amiodarone, and four others that have already progressed to clinical trials, induced phospholipidosis in the same concentration range as their antiviral activity; indeed, there was a strong monotonic correlation between antiviral efficacy and the magnitude of the phospholipidosis. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the gross physical properties of drugs, and does not reflect specific target-based activities, rather it may be considered a confound in early drug discovery. Understanding its role in infection, and detecting its effects rapidly, will allow the community to better distinguish between drugs and lead compounds that more directly impact COVID-19 from the large proportion of molecules that manifest this confounding effect, saving much time, effort and cost.One Sentence SummaryDrug-induced phospholipidosis is a single mechanism that may explain the in vitro efficacy of a wide-variety of therapeutics repurposed for COVID-19.

Myeloid bodies caused by COQ2 mutation: a case with the coincidence of COQ2 nephropathy and IgA nephropathy

IgA nephropathy (IgAN) combined with myeloid bodies have been reported in Fabry disease (FD). However, we excluded the diagnosis of FD by no mutation in GLA gene. And she denied the use of cationic amphiphilic drugs. Interestingly, we identified a novel missense mutation for COQ2, which can cause COQ2 mutation associated nephropathy. The patient we reported also had heteromorphic mitochondria, and a good curative effect after CoQ10 supplementation. Combined these, this patient was diagnosed with COQ2 nephropathy and IgAN. To our knowledge, this is the first case report that COQ2 nephropathy with pathologic manifestations of myeloid body in podocytes.