Unlike Chloroquine, mefloquine inhibits SARS-CoV-2 infection in physiologically relevant cells and does not induce viral variants

Abstract

Repositioning of clinical approved drugs could represent the fastest way to identify therapeutic options during public health emergencies, the majority of drugs explored for repurposing as antivirals for 2019 coronavirus disease (COVID-19) have failed to demonstrate clinical benefit. Without specific antivirals, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to cause major global mortality. Antimalarial drugs, such as chloroquine (CQ)/hydroxychloroquine (HCQ) and mefloquine have emerged as potential anti-SARS-CoV-2 antivirals. CQ/HCQ entered the Solidarity and RECOVERY clinical trials against COVID-19 and showed lack of efficacy. Importantly, mefloquine is not a 4-aminoquinoline like CQ and HCQ and has been previously repurposed for other respiratory diseases. Unlike the 4-aminoquinolines that accumulate in the high pH of intracellular lysosomes of the lung, the high respiratory tract penetration of mefloquine is driven by its high lipophilicity. While CQ and HCQ exhibit activity in Vero E6 cells, their activity is obviated in TMPRSS2-expressing cells, such as Calu-3 cells, which more accurately recapitulate in vivo entry mechanisms for SARS-CoV-2. Accordingly, here we report the anti-SARS-CoV-2 activity of mefloquine in Calu-3 type II pneumocytes and primary human monocytes. Mefloquine inhibited SARS-CoV-2 replication, including the gamma variant, in Calu-3 cells with low cytotoxicity and EC50 and EC90 values of 1.2 and 5.3 uM, respectively. In addition, mefloquine reduced up to 68% the SARS-CoV-2 RNA levels in infected monocytes, reducing viral-induced inflammation. Mefloquine blocked early steps of the SARS-CoV-2 replicative cycle and was less prone than CQ to induce drug-associated viral mutations and synergized with RNA polymerase inhibitor. The pharmacological parameters of mefloquine are consistent with its plasma exposure in humans and its tissue-to-plasma predicted coefficient points that this drug may accumulate in the lungs. These data indicate that mefloquine could represent an orally available clinically approved drug option against COVID-19 and should not be neglected on the basis of the failure of CQ and HCQ.

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…Nine of the approved drugs are formulated for oral use; interferon alpha and ciclesonide are inhaled therapeutics. Two other agents appeared to synergize with RDV in Calu3 cells but were tested only at two doses: the approved oral drug mefloquine ( 98 ) and the investigational drug brilacidin ( 88 ). Of the pairs in Table 1 , only the combination of MPV plus brequinar has been tested in an animal model, where it reduced viral loads and lung pathology favorably compared to either drug alone ( 77 ).…”

COVID-19 Therapeutic Potential of Natural Products

“…Combination therapy, which involves two or more therapeutic agents, has been a cornerstone of antiviral therapy. For example, combination treatment involving at least three different antiretroviral drugs (two nucleoside reverse transcriptase inhibitors, and one either an integrase strand transfer inhibitor (INSTI)-a non-nucleoside reverse transcriptase inhibitor-or a protease inhibitor) is recommended for the standard treatment of HIV [169]. Such a combination therapy could inhibit HIV replication, allowing the immune system to overcome the infection and prevent AIDS.…”

The Impact of SARS-CoV-2 nsp14 Proofreading on Nucleoside Antiviral Activity: Insights from Genetic and Pharmacological Investigations

“…Subsequent studies using polymerase extension assays demonstrated that those compounds can be incorporated by SARS-CoV-2 RdRp (11,12), disrupting the RNA synthesis by direct chain termination (11) or accumulation of deleterious mutations in viral genome (12). However, in the cell-based assays, inhibition of SARS-CoV-2 replication by those compounds were low or nondetectable (13)(14)(15).…”

“…Combination of NUCs with HCV NS5A inhibitors, which were predicted to target SARS-CoV-2 nsp14 exonuclease domain, increased the antiviral potency of NUCs against SARS-CoV-2 (13,14).…”