A guest blog from Gillian de Villiers in my lab – thanks, Gillian!
FGI-104: A broad-spectrum small molecule inhibitor of viral infection.
Am J Transl Res 2009; 1:87-98
Essentially there is a lack of treatment options for viral threats, especially should a new, hitherto unknown virus become prominent. Vaccines take substantial time to develop, and most anti-viral agents are highly specific to only one virus and in targeting viral proteins place strong selection pressure on the viruses, causing resistance to evolve swiftly.
Since most viruses exploit the same small set of host molecules, and hijack these systems for their own replication, if such molecules could be targeted it could be a very effective approach and is known as “host-directed therapeutics”. A development stage company called Functional Genetics, Inc. (FGI) is involved in research in this field.
One of the “housekeeping” molecules is TSG101, it usually escorts proteins that are to be degraded and is a positive regulator of the budding process. After a virus has infected a cell, TSG101 moves newly formed viruses from the cell interior to the outer membrane. This mechanism is shared by a broad range of virus families and therefore is a potential anti-viral target.
FGI selected a library of small molecule compounds with apparent ability to block TSG101 and checked for ability to block viral replication. There is no detail on where this library came from, or what kind of molecules they are. At http://www.faqs.org/patents/asn/32771 a number of patents by FGI are available, but as they generalise the family of compounds, on my brief reading I was unable to determine the chemical structure of the one molecule used in this study: FGI-104. There is also no reference to any other scientific article in the paper that could give an idea what this compound is, but it would have been good to know.
CONCLUSIONS and COMMENTS
The authors were able to show that their compound FGI-104 has anti-viral activity against a broad range of viruses, although it did not have activity against influenza viruses (data not shown). They do not make it clear what the actual structure is of compound FGI-104, or how the screened library of compounds was chosen. They were able to show that the antiviral activity does not come from inhibition of viral nucleic acid replication. This makes sense as the antiviral compound FGI‑104 was chosen for its action against cell protein TSG101 which moves viruses to the exterior in an infected cell.
They mention some work on viruses for which data is not shown, except for the Table, and more importantly, for which no information is given in the method section. Their lethal Ebola mouse study is very striking, as it shows extension of life of animals exposed to a mouse Ebola when treated with the compound FGI‑104, where untreated controls died. In addition when rechallenged the mice survived. However the number of mice used is not made clear, there was an untreated control group (n unknown), and group of mice daily treated with FGI‑104 for 10 days (n unknown). The article hints at a further group of mice treated less extensively, but this is almost pure speculation as the article has the same lack of detail as a cookbook from the 1500s. I feel the methods section is therefore somewhat lacking.
What is significant, looking at the Table, is the variation in dose required for activity against the different viruses. For example, while for HBV the EC50 (effective half-maximal concentration: concentration is half-way between baseline and maximum) is only 0.02uM, for Ebola it is 8uM. The different cell lines also have different CC50 (concentration that kills 50% of host cells) levels. What is also striking is that while, for example, for Ebola the CC50 is only 5X the EC50, making the safety margin quite narrow, it is clear that it is better to be a mouse treated with FGI‑104 (whether toxic at that dose or not) if you are a mouse unfortunate enough to be exposed to Ebola virus. For most of the viruses however the safety margin was quite large, which is just as well as with further pharmaceutical testing through the various clinical trials, and even after approval, apparently new information tends to show the safety margin to be smaller than first calculated. I do not know what is considered a “suitable” safety margin for a pharmaceutical.
The field of host-targeted therapeutics appears to be a promising angle in development of anti-virals with a reasonably broad-spectrum of activity. Another article “Targeting inside-out phosptidylserine as a therapeutic strategy for viral diseases” (Nature Medicine 14:12, Dec 2008) by an unrelated group showed the use of a chimeric antibody against inside out phosphatidyl-serine molecules, a marker of viral infection on host cells, to be effective in controlling viral infection. Both of these articles were cited in the New Scientist article “How to cure diseases before they have even evolved” (Issue 2720, Aug 2009). These drugs may one day buy time before a vaccine is available for new virulent viruses, but even if the host molecules are being targeted, I am convinced that viral resistance will only be a matter of time…
Link to full report: Broadspectrum antiviral