Targeting TMEM16F‑Driven Membrane Remodeling: A Promising Strategy for Broad-Spectrum Antiviral Development

With the continuous rise of epidemics with potential for global threats, the need for antiviral drug development continues to be essential. Most drugs approved by the Food and Drug Administration (FDA) are direct-acting agents (DAAs), targeting specific viral proteins, thus restricting the range of applications of the antiviral. Due to the constant evolution of viruses, DAAs regularly have to be optimized or modified to maintain their inhibitory effect against emerging resistant variants. An alternative therapeutic approach to DAAs are host-directed agents (HDAs) which instead target host processes to inhibit viral infection. They offer more potential for broad-spectrum use if the targeted host processes are conserved across viral families. They are also more resistant to viral mutations. However, research has to be done to identify such strategic host targets. Previous work done on TMEM16F, a cell membrane Ca2+-activated scramblase, has identified it as an interesting candidate for host-directed antiviral strategies. TMEM16F’s role in phosphatidylserine (PS) translocation from the inner leaflet of the cell membrane to the outer leaflet is essential for microvesicle secretion. However, research has shown TMEM16F can be hijacked by viruses, such as Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), for viral apoptotic mimicry and for cell fusion, respectively. By activating TMEM16F for PS translocation, membrane-derived viral envelopes may contain this phospholipid, enabling glycoprotein-independent viral entry and dissemination into a host. The extent to which different virus families utilize this scramblase for viral spread and immune evasion remains to be elucidated. Niclosamide, an FDA-approved anthelminthic drug, was found to inhibit TMEM16F scramblase activity. Drug screening also revealed antiviral activity against SARS-CoV-2. While niclosamide has shown antiviral, antibacterial and anticancer potential, it has low bioavailability and can cause severe side effects at high dosage. Since TMEM16F’s 3D structure was resolved with cryo-electron microscopy along with niclosamide’s binding pocket, AI-driven drug analog design may be used to optimize the drug’s efficacy and minimize cytotoxicity. Thus, in this paper, we will consider whether targeting TMEM16F scramblase activity offers broad-spectrum antiviral potential and whether niclosamide can be repurposed and optimized as a pan-viral HDA.