Monday 25th of May 2020

back in 2017...


ONLINE COVER Bat-tling Zoonotic Infections. Coronaviruses are endemic in multiple mammalian species, including bats, and can jump into the naïve human population at anytime. Sheahan et al. identified an antiviral drug that had activity against coronaviruses from various hosts. Their findings indicate this drug could be useful during the next zoonotic coronavirus outbreak. [CREDIT: BLICKWINKEL/ALAMY STOCK PHOTO]

members cycle in and out of humans and zoonotic hosts...


Emerging viral infections are difficult to control because 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. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (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. 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 function. 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.


The genetically diverse coronavirus (CoV) family, currently composed of four genogroups [1 (alpha), 2 (beta), 3 (gamma), and 4 (delta)], infects birds and a variety of mammals. Thus far, only CoV groups 1 and 2 are known to infect humans. Although CoV replication machinery exhibits substantial proofreading activity, replication of viral genomic RNA is inherently error-prone, driving the existence of genetically related yet diverse quasi-species (1). Most CoV strains are narrow in their host range, but zoonotic CoVs have a proclivity to jump into new host species (2). Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) are recent examples of newly emerging CoV that caused severe disease in immunologically naïve human populations. SARS-CoV emerged in Guangdong, China in 2002 and, with the aid of commercial air travel, spread rapidly throughout the globe, causing more than 8000 cases with 10% mortality (2). In 2012, it was discovered that MERS-CoV evolved to infect humans through bats by way of an intermediate camel host, causing more than 1700 cases with almost 40% mortality and, like SARS-CoV, air travel has fueled global spread to 27 countries (2). MERS-CoV is endemic in the Middle East, and serologic studies in the Kingdom of Saudi Arabia and Kenya suggest fairly frequent infections in humans (>45,000 persons) (3, 4). The SARS-CoV epidemic ended over a decade ago, but several SARS-like CoVs have been isolated from bats that efficiently use the human angiotensin-converting enzyme 2 receptor, replicate to high titer in primary human airway cells, and are resistant to existing therapeutic antibodies and vaccines (5, 6). With increasing overlap of human and wild animal ecologies, the potential for novel CoV emergence into humans is great (2). Broad-spectrum CoV therapies capable of inhibiting known human CoV would address an immediate unmet medical need and could be an invaluable treatment in the event of novel CoV emergence in the future.

Currently, there are no approved specific antiviral therapies for CoV in humans. Attempts made to treat both SARS-CoV and MERS-CoV patients with approved antivirals (that is, ribavirin and lopinavir-ritonavir) and immunomodulators (that is, corticosteroids, interferons, etc.) have not been effective in randomized controlled trials (7). Clinical development of effective CoV-specific direct-acting antivirals (DAAs) has been elusive, although there are several conserved druggable CoV enzyme targets including 3C-like protease, papain-like protease, and nonstructural protein 12 (nsp12) RNA-dependent RNA polymerase (RdRp) (7). In 2016, Warren et al. reported the in vivo antiviral efficacy of a small-molecule monophosphoramidate prodrug of an adenosine analog, GS-5734, against Ebola virus in nonhuman primates (8). Because the mechanism of action of GS-5734 for Ebola virus is the inhibition of the viral RdRp and previous work had suggested weak activity of the nucleoside component of GS-5734 against SARS-CoV (9), we sought to assess the antiviral potency and breadth of activity of GS-5734 against a diverse panel of human and zoonotic CoV.


Read more:

Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaal3653