Broad-spectrum coronavirus antiviral drug discovery

ABSTRACT

Introduction: The highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are lethal zoonotic viruses that have emerged into human populations these past 15 years. These coronaviruses are associated with novel respiratory syndromes that spread from person-to-person via close contact, resulting in high morbidity and mortality caused by the progression to Acute Respiratory Distress Syndrome (ARDS).

Areas covered: The risks of re-emergence of SARS-CoV from bat reservoir hosts, the persistence of MERS-CoV circulation, and the potential for future emergence of novel coronaviruses indicate antiviral drug discovery will require activity against multiple coronaviruses. In this review, approaches that antagonize viral nonstructural proteins, neutralize structural proteins, or modulate essential host elements of viral infection with varying levels of efficacy in models of highly pathogenic coronavirus disease are discussed.

Expert opinion: Treatment of SARS and MERS in outbreak settings has focused on therapeutics with general antiviral activity and good safety profiles rather than efficacy data provided by cellular, rodent, or nonhuman primate models of highly pathogenic coronavirus infection. Based on lessons learned from SARS and MERS outbreaks, lack of drugs capable of pan-coronavirus antiviral activity increases the vulnerability of public health systems to a highly pathogenic coronavirus pandemic.

KEYWORDS:

• Antiviral
• ARDS
• acute respiratory distress syndrome
• bat
• broad-spectrum
• camel
• civet
• coronavirus
• emerging virus
• highly pathogenic virus
• human cases
• interferon
• in vitro model
• lopinavir
• MERS
• MERS-CoV
• Middle East respiratory syndrome
• pneumonia
• primate model
• respiratory
• ribavirin
• rodent model
• SARS
• SARS-CoV
• severe acute respiratory syndrome
• therapeutic
• zoonosis
• zoonotic

Article Highlights

• Broad-spectrum drugs targeting coronaviruses must have efficacy against known highly pathogenic human coronaviruses SARS-CoV and MERS-CoV, but also have activity against additional novel coronaviruses that may emerge in the future.

• Conventional approaches identifying adaptive-based therapeutics like vaccines and monoclonal antibodies against coronaviruses target antigens that are not conserved and are unlikely to retain therapeutic efficacy against diverse coronavirus pathogens.

• Reverse genetics approaches that generate novel coronaviruses currently circulating in bats are an innovative but under-utilized resource to provide additional zoonotic and pre-emergent virus diversity to in vitro and in vivo drug discovery platforms.

• Many of the treatments used in SARS or MERS patients in outbreak situations were not based on clear in vitro and in vivo model evidence of efficacy, and meta-analyses of treatments failed to show effective therapeutic regimens.

• Development of a drug discovery pipeline consisting of in vitro and in vivo models of coronavirus infection is needed to identify antivirals targeting essential mechanisms of infection.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was supported in part by an appointment to the Postgraduate Research Participation Program at the US Army Medical Research Institute of Infectious Diseases administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Army Medical Research and Materiel Command (USAMRMC).