The broad spectrum host-directed agent ivermectin as an antiviral for SARS-CoV-2 ?

Abstract

FDA approved for parasitic indications, the small molecule ivermectin has been the focus of growing attention in the last 8 years due to its potential as an antiviral. We first identified ivermectin in a high throughput compound library screen as an agent potently able to inhibit recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host importin (IMP) α/β1 heterodimer, and recently demonstrated its ability to bind directly to IMPα to cause conformational changes that prevent its function in nuclear import of key viral as well as host proteins. Cell culture experiments have shown robust antiviral action towards a whole range of viruses, including HIV-1, dengue, Zika and West Nile Virus, Venezuelan equine encephalitis virus, Chikungunya, pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Close to 70 clinical trials are currently in progress worldwide for SARS-CoV-2. Although few of these studies have been completed, the results that are available, as well as those from observational/retrospective studies, indicate clinical benefit. Here we discuss the case for ivermectin as a host-directed broad-spectrum antiviral agent, including for SARS-CoV-2.

Keywords: Antiviral; COVID-19; Dengue virus; Ivermectin; SARS-CoV-2; Zika virus.

Fig. 1

Model of 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 NF-κB transcription factor family localize in the nucleus through IMPα/β1, where the “IBB” (IMPβ-binding) region of IMPα (purple curved line) is bound by IMPβ1 to enable cargo recognition by IMPα within the heterodimer. Subsequently, IMPβ1 mediates transport of the trimeric complex into the nucleus through the nuclear envelope (NE)-embedded nuclear pore (NPC, nuclear pore complex). Release within the nucleus enables the transcription factor to carry out normal function in transcriptional regulation, including in the antiviral response. IMPα cannot mediate nuclear import, unless heterodimerised with IMPβ1. B. In viral infection, specific viral proteins (eg. NS5 in the case of DENV, ZIKV) 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 for optimal virus production as shown by mutagenic and inhibitor studies. The SARS-CoV-2 proteins that may access the nucleus via IMPα/β1 in infected cells has not been examined, but in ORF6 (Open Reading Frame 6) protein from SARS-CoV1 has been shown to bind IMPα [29], and ORF4b from MERS-CoV (Middle Eastern Respiratory Syndrome Coronavirus) are both known to access the nucleus in NLS-dependent fashion [30]. C. The small molecule ivermectin (structure shown) 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 preventing NS5 nuclear import [11], contributing to reduced virus production. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)