The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors

Abstract

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock.

Cyclophilin A: A Key Factor in Virus Replication and Potential Target for Anti-viral Therapy

“…Cellular CypA is the vital binding partner with N protein of SARS-CoV (Luo et al, 2004). A study using unbiased yeasttwo-hybrid screening discovered that CypA bind to Nsp1 protein of SARS-CoV (Pfefferle et al, 2011) and HCoV-NL63 virus. The nucleocapsid (N) protein of SARS-CoV interacts with CypA, which mediates HAb18G/ CD147 to interact with SARS-CoV N protein, and thus helps in viral replication in 293 cells (Chen et al, 2005).…”

What are our pharmacotherapeutic options for MERS-CoV?

“…Mycophenolic acid showed strong inhibition of MERS-CoV in vitro [12]. Cyclosporine A inhibits cyclophilins by blocking the replication of all coronavirus genera, including SARS-CoV [13]. Cyclosporine A was also identified as an inhibitor of MERS-CoV replication in cell culture [14].…”

Cyclosporin A Inhibits the Propagation of Influenza Virus by Interfering with a Late Event in the Virus Life Cycle

“…CsA reportedly inhibits the replication of various viruses such as human immunodeficiency virus type-1, hepatitis C virus, coronaviruses, vaccinia virus, vesicular stomatitis virus, herpes simplex virus, and BK polyomavirus (9)(10)(11)(12)(13)(14)(21)(22)(23)(24)(25)(26). CsA has antiviral effects on a wide range of viruses; therefore, we hypothesized that CsA would inhibit the multiplication of influenza virus.…”