Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2<i>in vitro</i>, Evidencing<i>S</i>-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

Li, Guanguan; Sun, Jing; Huang, Yi‐You; Li, Yingjun; Shi, Yongjie; Li, Zhe; Li, Xiang; Yang, Feng; Zhao, Jincun; Luo, Hai‐Bin; Zhang, Tony Y.; Zhang, Xumu

doi:10.1101/2020.05.26.114033

Cited by 13 publications

(18 citation statements)

References 73 publications

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“…HCQ is formulated as the racemate of its R and S enantiomers, and both were found to be active in vitro by blocking SARS-CoV-2 infection in the low micromolar range, with the S stereoisomer being slightly more active that the R stereoisomer. 12 Therefore, both the S and R enantiomers served as templates for virtual screening, and only the top GP generated from R -HCQ and S -HCQ forms for the final ranking of the single screened drug were selected. When more than one form of the screened drug ( e.g ., more than one enantiomer, more than one protomer, etc.)…”

Section: Methodsmentioning

confidence: 99%

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Bocci

Bradfute

et al. 2020

ACS Pharmacol. Transl. Sci.

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The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC 50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite ( N -monodesethyl amodiaquine) is also discussed. In trying to understand the “hydroxychloroquine” mechanism of action, both p K a and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics.

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Section: Methodsmentioning

confidence: 99%

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Bocci

Bradfute

et al. 2020

ACS Pharmacol. Transl. Sci.

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“…A study conducted by Guanguan Li et al concluded that the enantiomers of CQ and HCQ act differently against SARS-CoV-2, and S enantiomers were found to be more effective. S enantiomers showed a better hERG inhibition and M pro activity in vitro as well as S-HCQ in vivo QT prolongation than R enantiomers [ 90 ].…”

Section: Pharmacological Treatment With Promising Clinical Benefitsmentioning

confidence: 99%

The controversial therapeutic journey of chloroquine and hydroxychloroquine in the battle against SARS-CoV-2: A comprehensive review

Das

Ramachandran

Birangal

et al. 2021

Medicine in Drug Discovery

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Recently, the pandemic outbreak of a novel coronavirus, officially termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indicated by a pulmonary infection in humans, has become one of the most significant challenges for public health. In the current fight against coronavirus disease-2019, the medical and health authorities across the world focused on quick diagnosis and isolation of patients; meanwhile, researchers worldwide are exploring the possibility of developing vaccines and novel therapeutic options to combat this deadly disease. Recently, based on various small clinical observations, uncontrolled case studies and previously reported antiviral activity against SARS-CoV-1 chloroquine (CQ) and hydroxychloroquine (HCQ) have attracted exceptional consideration as possible therapeutic agents against SARS-CoV-2. However, there are reports on little to no effect of CQ or HCQ against SARS-CoV-2, and many reports have raised concerns about their cardiac toxicity. Here, in this review, we examine the chemistry, molecular mechanism, and pharmacology, including the current scenario and future prospects of CQ or HCQ in the treatment of SARS-CoV-2.

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“…It has been demonstrated that S-CQ has a higher antimalarial activity than R-CQ [38]. Results from in vitro antiviral activity against SARS-CoV-2 in Vero E6 cells showed that both CQ and HCQ enantiomers exhibited antiviral effect in a concentration-dependent manner.…”

Section: Cq and Hcq Stereopharmacologymentioning

confidence: 99%

Chloroquine and Hydroxychloroquine: how about switching?

Novotný¹,

Monteiro²,

Lima³

et al. 2021

JPPR

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Early studies suggesting that chloroquine (CQ) and hydroxychloroquine (HCQ) could benefit coronavirus patients brought these old medicines back to the spotlight. This led to an increase in demand and price, turning their counterfeiting a pharmacovigilance issue worldwide. Meanwhile, lack of evidence on effectiveness and safety concerns have reduced their clinical trials in severe COVID-19 cases. Despite the knowledge that CQ and HCQ toxic effects are stereo specific rather than their therapeutic effects, these drugs are available only as racemates. In this context, this work brings a discussion about chiral switching to their eutomers so that CQ and HCQ distomers would become impurities, what may be a viable alternative to test new dose-response curves. Even if it is proven that the use of pure CQ and HCQ enantiomers are useless against COVID-19, chiral switching would certainly improve safety and efficacy in the treatment of many autoimmune inflammatory diseases, benefiting chronic users of these drugs.

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Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2in vitro, EvidencingS-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

Cited by 13 publications

References 73 publications

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

The controversial therapeutic journey of chloroquine and hydroxychloroquine in the battle against SARS-CoV-2: A comprehensive review

Chloroquine and Hydroxychloroquine: how about switching?

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