Anti-SARS-CoV-2 Action of 5α-Reductase Inhibitors May Be Mediated by Dehydroepiandrosterone. Letter.

Abstract

We read with interest the study of Lyon et al. 1 5α-reductase inhibitor (5ARIs)-induced testosterone (T) and androstenedione (A4) increase may shunt these precursors to estrogens.Additional precursor steroids maybe involved and more plausibly account for the observation of reduction in community acquired severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. 1 Dutasteride decreases the formation of T, dihydrotestosterone (DHT) and precursor steroids in the backdoor pathway but increases steroid precursors, including dehydroepiandrosterone (DHEA), in the classical steroidogenesis pathway while finasteride despite a significant decrease in the non-sulfated DHEA leads to an accumulation of DHEA-Sulfate (DHEAS) in rats. 2,3 In post-finasteride patients, DHEA is increased both in plasma and central nervous system. 4 Both DHEA/DHEAS are moderate endogenous sigma 1 receptor (S1R) agonists (DHEA (Ki = 2.96 µM), DHEAS (Ki = 15.13 µM)), and similarly to the potent exogenous agonist fluvoxamine (Ki= 36nM), DHEA treatments may engender anti-SARS-CoV-2 protection through their S1Rmedated cardioprotective properties. 5,6 DHEA administration ameliorates pressure overloadinduced and transverse aortic constriction-induced cardiac hypertrophy and contractile dysfunction by upregulation of the S1R protein levels and activation the p-Akt-endothelial nitric

Multi-omics analysis uncovered systemic lupus erythematosus and COVID-19 crosstalk

“…Among them, the antithrombotic drug suloctidil was highlighted as the top therapeutic candidate, possibly due to its targeting of widespread vascular thrombotic events associated with COVID-19 and SLE (Farge et al 2022 ; Andreoli et al 2017 ). The steroid hormone prasterone, a common immunomodulator in SLE, also effectively manages disease activity and is believed to be a key mediator in the anti-COVID-19 action of 5α-reductase inhibitors (Durcan and Petri 2016 ; Papadopoulos et al 2022 ). Moreover, propofol, often used for intubation sedation in patients with COVID-19, exhibits direct anti-COVID-19 effects by inhibiting sigma-1 receptors in vitro.…”

Fluvoxamine Mediates Specific, Early, and Delayed SARS-CoV-2 Protection through Antioxidant and Cytoprotective Pathways via Sigma-1 Receptor Agonism

“…1,2 Fluvoxamine's mechanisms of action in COVID-19 have been extensively discussed and is mainly mediated via its potent (Ki=36 nM) sigma-1 receptor (sigma-1R, σ1R, S1R) agonism. [3][4][5] Sigma-1R interferes with the early steps of virus-induced host cell reprogramming and protect against mitochondrial damage and endoplasmic reticulum (ER) stress in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. 4 The reduction of cytokine production as indicated by sigma-1R's key role in systemic inflammation is supported by substantial evidence.…”

“…12 Sigma-1R's direct and AMPK-mediated-indirect effects on eNOS levels and phosphorylation, synergistically increase NO-production and bioavailability that underlie fluvoxamine's and DHEA's cardio-and vasculo-protective actions and mechanistically support specific and immediate anti-SARS-CoV-2 effects. 3,5 Increased NO-generation and bioavailability may counteract SARS-CoV-2-induced endotheliitis and even inhibit SARS-CoV-2 replication and infection at an early stage as shown by the inhibition of 1) the palmitoylation of the SARS-CoV-1/2 spike protein, essential for fusion to the angiotensin converting enzyme (ACE)2, its obligate receptor, and 2) early production of viral RNA by inhibiting SARS-CoV-2 main protease. Both these processes are critical for membrane fusion and virion infectivity.…”