Antivirals that target the host IMPα/β1-virus interface

Abstract

Although transport into the nucleus mediated by the importin (IMP) α/β1-heterodimer is central to viral infection, small molecule inhibitors of IMPα/β1-dependent nuclear import have only been described and shown to have antiviral activity in the last decade. Their robust antiviral activity is due to the strong reliance of many different viruses, including RNA viruses such as human immunodeficiency virus-1 (HIV-1), dengue (DENV), and Zika (ZIKV), on the IMPα/β1-virus interface. High-throughput compound screens have identified many agents that specifically target this interface. Of these, agents targeting IMPα/β1 directly include the FDA-approved macrocyclic lactone ivermectin, which has documented broad-spectrum activity against a whole range of viruses, including HIV-1, DENV1–4, ZIKV, West Nile virus (WNV), Venezuelan equine encephalitis virus, chikungunya, and most recently, SARS-CoV-2 (COVID-19). Ivermectin has thus far been tested in Phase III human clinical trials for DENV, while there are currently close to 80 trials in progress worldwide for SARS-CoV-2; preliminary results for randomised clinical trials (RCTs) as well as observational/retrospective studies are consistent with ivermectin affording clinical benefit. Agents that target the viral component of the IMPα/β1-virus interface include N-(4-hydroxyphenyl) retinamide (4-HPR), which specifically targets DENV/ZIKV/WNV non-structural protein 5 (NS5). 4-HPR has been shown to be a potent inhibitor of infection by DENV1–4, including in an antibody-dependent enhanced animal challenge model, as well as ZIKV, with Phase II clinical challenge trials planned. The results from rigorous RCTs will help determine the therapeutic potential of the IMPα/β1-virus interface as a target for antiviral development.

RETRACTED: Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon

“…The wide spectrum efficacy was assumed to be due to the dependency of several different RNA viruses on IMPα/β1 upon culminating infection [19,20]. Contextually, SARS-CoV protein experiments have demonstrated a possible function for IMP alpha/β1 throughout infection in signal-dependent nucleocytoplasmic SARS-CoV protein shutdown [21]. Moreover, the SARS-CoV attachment protein ORF6 was demonstrated to antagonize the antiviral action of the STAT1 transcription factor.…”

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

“…These observations correspond to the mechanism of action described for ivermectin in this context, which has been determined as a direct binding to IMPα, leading to structural changes that result in greater flexibility. These changes in IMPα1 have been reported to prevent interaction with the virus, as well as IMPβ1, and that the IMPα-dependent mode of action of ivermectin explains the wide range of viruses for which ivermectin has demonstrated antiviral effects both in vitro and in vivo [29] .…”

“…As the nuclear import for macromolecules is facilitated by importins, the structures of importin α1 subunit (PDB: 5KLR) from Mus musculus and importin β1 subunit (PDB: 2P8Q) from Homo sapiens were used as a model for the members of the nuclear import superfamily. The host nuclear import system can be bound and sequestered by pathogens such as SARS-CoV-2 allowing transportation of viral proteins to the host nucleus leading to increased viral replication [25] , [26] , [27] , [28] , [29] . Additionally, we also consider the multi-functional helicase (nsp13) of SARS-CoV-2 responsible for viral replication (PDB: 6ZSL) [30] , [31] , [32] , and the main protease (Mpro) of SARS-CoV-2 (PDB: 6LU7) as it is a key enzyme of coronaviruses and has a fundamental role in mediating viral replication and transcription, making it an attractive target for drugs [33] , [34] , [35] , [36] , [37] .…”

Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

“…As the nuclear import for macromolecules is facilitated by importins, the structures of importin α1 subunit (PDB: 5KLR ) from Mus musculus and importin β1 subunit (PDB: 2P8Q ) from Homo sapiens were used as a model for the members of the nuclear import superfamily. The host nuclear import system can be bound and sequestered by pathogens such as SARS-CoV-2 allowing transportation of viral proteins to the host nucleus leading to increased viral replication [ [12] , [13] , [14] , [15] ]. Additionally, we also consider the multi-functional helicase (nsp13) of SARS-CoV-2 responsible for viral replication (PDB: 6ZSL ) [ [16] , [17] , [18] ], and the main protease (Mpro) of SARS-CoV-2 (PDB: 6LU7 ) as it is a key enzyme of coronaviruses and has a fundamental role in mediating viral replication and transcription, making it an attractive target for drugs [ 11 , [19] , [20] , [21] , [22] ].…”