Highly Specific Sigma Receptor Ligands Exhibit Anti-viral Properties in SARS-CoV-2 Infected Cells

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.

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.

In Pursuit of Fluorinated Sigma Receptor Ligand Candidates Related to [18F]-FPS

This paper describes the synthesis of N-arylmethyl(1-benzyl) and N-aroyl(1-benzoyl) 4-(4-fluoromethylphenoxymethyl)piperidines as potential sigma receptor ligands analogous to the potent and highly selective sigma-1 ligand [18F]-FPS, but with enhanced or alternative binding and transport profiles. The synthesis involves N-aroylation of 4-hydroxmethylpiperidine or ethyl nipecotate, functional group manipulation of the ester group or simple activation of the hydroxyl group to introduce the phenoxy component, and subsequent functional group manipulation to reduce the amide group and introduce the fluorine into the fluoromethyl substituent. In its development, the synthesis was found to require early N-aroylation of the piperidine precursor to avoid complications due to anchimeric assistance by its nitrogen in subsequent displacement reactions. New evidence is presented on the pathway followed in a literature report of direct displacement of a benzylic hydroxyl group by fluoride ion under Appel-like conditions. Relevant to the literature report, the halide ion in the fluoromethylphenoxy 1-benzylpiperidine derivatives was surprisingly labile to hydrolytic displacement on chromatography and this aspect is worthy of further study. Moreover, the NMR spectra of the amides were complicated by geometric isomerism about the amide C(O)–N bond, but detailed analysis of spectra from 2-anisoyl derivatives allowed the assignment of diastereomeric contributors to consistent, secondary atropisomerism about the aryl–C(O) bond.