Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Abstract

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/β1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; Zika virus; antiviral; dengue virus; flavivirus; ivermectin.

Figure 1

Schematic showing IMPα’s role in nuclear transport of host and viral proteins, and mechanism of inhibition by ivermectin. (a) Host proteins, such as members of the STAT or NF-κB transcription factor families, localize in the nucleus through the action of the IMPα/β1 heterodimer, where the “IBB” (IMPβ-binding) region of IMPα (green curved line) is bound by IMPβ1 to enable cargo recognition by IMPα within the heterodimer; IMPβ1 subsequently mediates transport of the trimeric complex through the nuclear pore (NPC, nuclear pore complex) embedded within the nuclear envelope (NE) into the nucleus. This is followed by release within the nucleus to enable the transcription factors to carry out normal function in transcriptional regulation, including in the antiviral response. IMPα can only mediate nuclear import within the heterodimer with IMPβ1. (b) In viral infection, specific viral proteins (e.g., NS5 in the case of DENV, ZIKV, WNV) able to interact with IMPα utilize the IMPα/β1 heterodimer to access the nucleus and antagonize the antiviral response [14,27,28]. This is critical to enable optimal virus production as shown by mutagenic and inhibitor studies. Which SARS-CoV-2 proteins may access the nucleus in infected cells has not been examined (see Section 3). (c) The IMPα targeting compound ivermectin binds to IMPα (binding site shown as red lozenge) both within the IMPα/β heterodimer to dissociate it, and to free IMPα to prevent it binding to IMPβ1, thereby blocking NS5 nuclear import [11]. GW5074 (see Table 1) has been shown to exhibit a similar mechanism [29].