Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China

Abstract

A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain, providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).

Keywords: 2019-nCoV; ACE2; Wuhan; coronavirus; neutralizing antibody; outbreak.

Figure 1.. Therapeutic agents that could be used to block 2019-nCoV from infecting cells.

Target cells expressing ACE2 include lung and gastrointestinal tissues in the human body. The large spike protein on the surface of the coronavirus binds to ACE2 on infected cells, leading to cell entry. Three proposed strategies would block this interaction would abrogate infection. In the first, the receptor-binding domain (RBD) of the spike protein from SARS or 2019-nCoV would be administered, thereby binding ACE2 and saturating available sites. Alternatively, an antibody or single chain antibody fragment (scFv) could be administered against ACE2 to accomplish the same. A third strategy would target the coronavirus virions directly by using the ACE2 extracellular domain as bait to bind to spike protein. An Fc domain fused to ACE2 would facilitate prolonged circulation of the biologic (ACE2-Fc).

Figure 2.. TherapeuticDesign of the ACE2-Fc fusion protein as a therapy against 2019-nCoV coronavirus.

( A) The extracellular domain of ACE2 is appended onto the human immunoglobulin Fc domain, including the hinge region. The Fc domain facilitates dimerization of two ACE2 domains. ( B) The amino acid sequence of the ACE2-Fc fusion protein is provided. The ACE2 domain consists of amino acids 18–615 of the human ACE2 protein (blue; UniProtKB - Q9BYF1). The sequence of the human immunoglobulin G isotype 1 constant region is provided (green; UniProtKB - P01857). A secretion signal from a human immunoglobin heavy chain is provided (red; UniProtKB - A0A0C4DH39).