Currently, why there are few broad-spectrum anti-viral drugs
- The traditional anti-viral drug development blue-print focused on a specific virus.
- The goal was to try to prevent one of the following from happening, virus attachment, internalization, fusion, nuclear import-export, replication, protein synthesis, release from infected cells.
- The traditional process has been described as ‘one bug-one drug‘ (1) or as a ‘many for one‘ process (2).
- In this process, the goal was to find compounds that could block a particular target in a particular virus
- For example, compounds that inhibit Hepatitis C (HCV) protease and polymerase inhibitors (3).
- In combination, these drugs could potentially cure chronic HCV but as anyone who doesn’t live under a rock knows, this comes with a stupendous price tag.
- Other problems such as drug-drug interactions and drug resistance only emerge as problems over time.
- Recently, these long-standing notions are giving way to broad-spectrum anti-viral approaches (1), something that’s also described as the ‘one for many‘ approach (2), i.e., identifying compounds with broad-spectrum anti-viral properties.
- Broad-spectrum means capacity to target different viruses either within one family or even from different families, by targeting a particular viral infection approach, say, a particular method some viruses use to fuse with a cell.
- This approach hones in on common cellular factors and pathways that different viruses use.
- Since such pathways are likely ubiquitous, i.e., used by the cell as well, the key difficulty is to tease out the ones that viruses need for their replication but which are redundant for the cell.
- When pathway or factor is blocked, virus can’t replicate but cell has alternatives it could easily switch to.
- If not, toxicity induced by such drugs would outweigh potential benefits.
- This ratio between benefit and toxicity of a drug is called the Therapeutic index.
- In an ideal scenario, we seek drugs that, at a particular concentration, are 100% effective with 0% collateral damage, i.e., no toxicity.
- Ideal scenario is rarely, if ever, possible in reality.
- At any rate, the benefit-toxicity equation is nuanced, depending critically on treatment length.
- If short-term treatment rids of virus, a certain amount of toxicity may even be acceptable.
- The figure below (from 2) lists some of the advantages and disadvantages of broad-spectrum anti-viral capacity.
Existing and prospective broad-spectrum anti-viral drugs
- Effective against several RNA viruses, Ribavirin (4) is an example of an approved broad-spectrum anti-viral.
- Approved for use against RSV (Respiratory Syncytial virus) and HSV (Herpes Simplex virus), Ribavirin has no consensus mechanism of action (MoA) probably because it has several.
- Arbidol/Umifenoviris a broad-spectrum anti-viral for respiratory infections. Used in Russia and China (5).
- PERLs (polyunstaurated ER-targeting liposomes) are a serendipitous discovery of broad-spectrum anti-viral activity. A family of molecules, originally developed as anti-viral drug carriers, they themselves turned out to have potent broad-spectrum anti-viral activity, active against HIV, HBV and HCV (6).
- Nitazoxanidewas originally identified as an anti-parasitic agent. Now it’s shown to inhibit a variety of RNA and DNA viruses, including HIV, IFV, Dengue, HBV, HCV, JEV (7).
- Figure below (from 2) has some examples of natural compounds with broad-spectrum anti-viral activity.
- They’re derived from an extremely diverse range of sources, algal/bacterial/fungus/plant/shark/ sponge.
- Another recently published table (from 1; see below) also lists a variety of prospective broad-spectrum anti-virals.
- Thus, recently published peer-reviewed literature suggests the field is converging on
- The necessity for developing broad-spectrum anti-virals.
- The approaches necessary for uncovering relatively safe broad-spectrum anti-virals.
- Over the next few years, experimental studies will likely whittle down these candidates.
- The ones that pass the therapeutic index test in in vitro and in animal model studies will undergo further development.
- Vigant, Frederic, Nuno C. Santos, and Benhur Lee. “Broad-spectrum antivirals against viral fusion.” Nature Reviews Microbiology 13.7 (2015): 426-437.
- Martinez, J. P., et al. “Antiviral drug discovery: broad-spectrum drugs from nature.” Natural product reports 32.1 (2015): 29-48.
- Manns, Michael P., and Thomas von Hahn. “Novel therapies for hepatitis C- one pill fits all?.” Nature Reviews Drug Discovery 12.8 (2013): 595-610.
- Beaucourt, Stéphanie, and Marco Vignuzzi. “Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance.” Current opinion in virology 8 (2014): 10-15.
- Blaising, Julie, Stephen J. Polyak, and Eve-Isabelle Pécheur. “Arbidol as a broad-spectrum antiviral: An update.” Antiviral research107 (2014): 84-94.
- Pollock, Stephanie, et al. “Polyunsaturated liposomes are antiviral against hepatitis B and C viruses and HIV by decreasing cholesterol levels in infected cells.” Proceedings of the National Academy of Sciences 107.40 (2010): 17176-17181.
- Rossignol, Jean-François. “Nitazoxanide: a first-in-class broad-spectrum antiviral agent.” Antiviral research110 (2014): 94-103.