Huang, Shar-yin (NCI)
Wang, Wenjie (NCI)
Wang, Weidong (NIA)
Saha, Sourav (NCI)
Zhang, Tianyi (National Institute on Aging)
Garcia-Blanco, Mariano (University of Texas Medical Branch)
Shi, Pei-Yong (University of Texas Medical Branch)
Tse-Dinh, Yuk-Ching (Florida International University)
Kennedy-Boone, Debbie (University of Texas Medical Branch)
Topoisomerase 3B (TOP3B) is the only topoisomerase that can act on RNA as well as DNA, and thus has been a target of interest for the development of cancer therapies and RNA viral infection therapies. In the context of cancer, TOP3B is not an essential gene, but a subset of cancer cells with pre-existing genome instability are particularly vulnerable to the inactivation of TOP3B. While inhibitors for other topoisomerases are among the most potent and widely used anticancer agents, there are no known inhibitors of TOP3B. In the context of RNA viral infections, TOP3B has been implicated as a host factor for the replication of positive strand RNA viruses, particularly flaviviruses (i.e., Zika, West Nile, and Dengue) and coronaviruses (i.e., SARS-Cov1 and -2). TOP3B RNA-cleavage complexes could be targeted and trapped by inhibitors, causing persistent RNA damage to block viral RNA replication. This mechanism resembles the one employed by inhibitors of topoisomerases 1 and 2, which block DNA replication of cancer cells. TOP3B inhibitors could thus be valuable RNA virus drugs and anticancer drugs. However, to date no TOP3B inhibitors have been approved for antiviral or anticancer applications.
Researchers at the NIH (NCI and NIA) and their collaborators have discovered a family of cyanine dyes that could be used for anticancer and/or antiviral applications. The compounds have been shown to induce and stabilize TOP3B-RNA cleavage complexes in vitro and inhibit coronavirus replication in vitro. For example, one compound was shown to inhibit mouse coronavirus (MHV) in vitro with an IC50 of ~20 nM and is more potent than the FDA-approved drug remdesivir. At 1 uM, the same compound was shown to also inhibit human SARS-Cov2 replication in vitro by 4 orders of magnitude. In addition, these compounds have been shown to inhibit Zika virus (Dakar strain) in vitro with comparable efficacy as another commonly used flavivirus inhibitor (NITD-008). Furthermore, in vivo evaluation of the compounds in a mouse model of MHV revealed the compounds remain safe at 0.1mg/kg, can significantly inhibit viral replication and suppress MHV levels in the lung after intranasal application. These data support the development of the cyanine dye compounds as antiviral drugs to combat COVID-19 and other pandemics caused by RNA viruses. Overall, these cyanine dye-based compounds are potent inhibitors of TOP3B.
The NCI is seeking co-development research collaborations and/or licensees to further develop these cyanine dye-based TOP3B inhibitors into antiviral and/or anticancer agents.
- First-in-class TOP3B inhibitors for both anticancer and antiviral applications
- Similar mechanism to currently used and approved TOP1 and TOP2 inhibitors, but for RNA versus DNA
- Time- and dose- dependent effect on RNA-TOP3 cleavage complexes
- Effective and potent inhibition of viral replication in vitro and in vivo
- COVID-19 and other RNA-viral infection therapy
- Anticancer agents
- Molecular probes to study the biology of TOP3B