Broad-spectrum coronavirus antiviral drug discovery

Abstract

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

Figure 1.

Coronavirus emergence from zoonotic reservoirs. Emergence of coronaviruses into human populations, including highly pathogenic viruses like SARS-CoV and MERS-CoV, has occurred by spillover from bat reservoir hosts into intermediate hosts. The intermediate hosts during the 2003 SARS-CoV epidemic included civets and other small carnivore species located in wet animal markets. MERS-CoV has been identified in dromedary camels, and is particularly associated with active infection of juvenile camels. Novel emerging CoVs may occur in the future via infection from bat populations into other intermediate animal hosts. Additional evidence from BatCoVs indicates that pre-emergent CoVs with the ability to directly infect human cells may be poised for emergence into human populations. Based on prior research from SARS and MERS outbreaks, animal workers that have contact with intermediate animal host species and health-care workers that are exposed to nosocomial CoV infections are at increased risk of highly pathogenic coronavirus transmission. More severe disease in SARS and MERS cases resulted in patients that were over the age of 65 or had comorbidities such as obesity, heart disease, diabetes, renal disease, or hypertension.

Figure 2.

Coronavirus virion structure and genomic organization. As an example of coronavirus virion (A) and genome (B) structure, a schematic of MERS-CoV (GenBank JX869059) is provided. Virions exist as enveloped viral particles, with the Spike (S), Membrane (M), and Envelope (E) proteins decorating the outside of the membrane. Coronaviruses in genogroup 2a have an additional structural protein hemagglutinin esterase (HE), which has been omitted from this discussion. Inside of the virion, the Nucleocapsid (N) protein encapsidates the viral genome. The viral genome is composed of + sense, single-stranded RNA. At the 5ʹ end of the genome, a single polyprotein open reading frame encodes the more highly conserved nonstructural proteins (ORF1a, ORF1b). At the 3ʹ end of the genome, the functionally conserved structural proteins that make up the virion are interspersed with virus-specific accessory proteins (ORF3, ORF4a, ORF4b, ORF5, and ORF 8b). Accessory proteins are conserved between very closely related viruses like BatCoV-HKU4, BatCoV-HKU5, and MERS-CoV. There is no conservation of accessory proteins between known HCoVs.

Figure 3.

Pan-coronavirus drug discovery. Currently, the state of pan-coronavirus drug discovery is not structured to provide adequate pre-clinical therapeutics to combat emerging CoV pathogens. A diverse array of coronaviruses is needed that includes epidemic isolates of SARS-CoV and MERS-CoV, zoonotic viruses isolated from intermediate reservoir hosts, pre-emergent CoVs from bats, and clinical isolates of mildly pathogenic HCoVs. In vitro testing in compatible cell lines uses high throughput screening to identify novel targets that mitigate replication of coronaviruses. Targets identified by in vitro methods can be confirmed using human airway epithelial cultures. Based on these results, lead targets will be tested in small animal models and nonhuman primate models of highly pathogenic coronavirus infections that recapitulate signs of human SARS or MERS patients. Our analysis identified several key weaknesses in both in vitro and in vivo models of highly pathogenic coronavirus virus infection impeding the identification of pan-coronavirus antiviral drugs.