Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Abstract

Emerging viral infections are difficult to control as heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. SARS-CoV and MERS-CoV successively emerged causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. Here we show that a nucleotide prodrug GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat-CoVs, prepandemic bat-CoVs and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory functions. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and possibly most importantly, emerging CoV of the future.

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

“…32 Preclinical evidence showed the potent efficacy of remdesivir (a broad-spectrum antiviral nucleotide prodrug) to treat MERS-CoV and SARS-CoV infections. 33,34 As 2019-nCoV is an emerging virus, an effective treatment has not been developed for disease resulting from this virus. Since the combination of lopinavir and ritonavir was already available in the designated hospital, a randomised controlled trial has been initiated quickly to assess the efficacy and safety of combined use of lopinavir and ritonavir in patients hospitalised with 2019-nCoV infection.…”

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019‐nCoV

“…[25][26][27] Despite computational modelsv alidated against known ATAt argets predicting RdRp as the bound target, no experimental evidence has demonstrated this relationship. [35] Broad-spectrum activity against various bat coronaviruses was also demonstrated. The nucleoside analogue ribavirin (RBV,F igure 4) has been tested against SARS-CoV,and in SARS-and MERS-infected patients.…”

“…[28] Beyond this exception,t he remainingR dRp inhibitors have been nucleoside analogues,a nd these provide the most promisinga venue towards disrupting viral RNA replication. [35] The susceptibility of CoV to remdesivir was shown to be increased in strains with inactivated exonuclease activity. [29][30][31][32] At best, efficacy with RBV was inconclusive, with some studies showing aw orsening of patient outcomes (as reviewed by Stockman, et al).…”

Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus

“…Remdesivir is an 105 adenosine nucleotide analogue prodrug with broad-spectrum antiviral activity against106 filoviruses, paramyxoviruses, pneumoviruses, and pathogenic coronaviruses, like SARS-CoV and 107 MERS-CoV(17). Moreover, social and economic issues 97 generated by this epidemic also call for rapid interventions.…”

“…Moreover, social and economic issues 97 generated by this epidemic also call for rapid interventions. Nevertheless, remdesivir was effective against SARS-CoV,111 MERS-CoV, and bat-CoV strains(17). Previous work with SARS-CoV and MERS-CoV has100 provided an opportunity to accelerate the identification of meaningful therapies for fighting promising antiviral for fighting SARS-CoV-2 is remdesivir.…”