The Future Of Antivirals In Medicine - Curing The Incurable?
Antibiotics have called a "magic bullet" in the fight against infectious diseases. This is because a single antibiotic may be capable of destroying a wide variety of bacterial infections, alleviating symptoms of illness complete in many cases. Antivirals have traditionally seen less success in combatting viral infections than their bacterial counterparts. Primarily this is a result of the specificity of typical anti-virals which means that most may only inhibit a single viral infection for as long as the treatment is prescribed. In addition, despite the media hysteria surrounding the potential threat of total antibiotic resistance, viruses mutate at a much faster rate than even bacteria, resulting in anti-virals losing their effectiveness in a very short period of time. In recent years, however, scientists have started to lay the foundations for the emergence of a new generation of broad-spectrum anti-virals capable of inhibiting (or even eradicating!) a variety of viral infections.
One of these broad-spectrum anti-virals currently under development by M.I.T. is D.R.A.C.O. (Double-Stranded RNA Activated Caspase Oligomerizer), a bioengineered microscopic super protein that "can identify cells that have been infected by any type of virus, then kill those cells to terminate the infection" [1]. Under laboratory conditions D.R.A.C.O. has already proven to be "non-toxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arena viruses, Guama bunyavirus, and H1N1 influenza" [2] [2] D.R.A.C.O. “selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells” [3], it is important to note that dsRNA is present in almost all virally infected cells but its absent in healthy cells making it a perfect marker. However, some scientists have noted that D.R.A.C.O. is still a long way off from being developed into an actual therapy, detailing how “several sets of trials in larger animals (and eventually humans) will have to meet with success between now and then” [4]. It is important to note that D.R.A.C.O. has only been trialled and successfully eradicated 15 viral infections in vitro and only 2 viral infections in mice and is thus still very much in its early stages towards becoming a viable therapy. Furthermore, D.R.A.C.O. is made up of large super-proteins and as a result oral delivery is unlikely and will likely have to be administered in injection form. This would mean that D.R.A.C.O. would only be used for serious viral infections, as opposed to more common infections such as the rhinovirus, which M.I.T. have mainly trialled D.R.A.C.O. against to date.
Another potential broad-spectrum antiviral, which has demonstrated encouraging results in laboratory testing, is Squalamine. Squalamine is “a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), [which] exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo.” [5] The scientist’s began looking for molecules with antiviral properties in sharks, as they are remarkably resistant to viral infections despite having no rapidly responsive adaptive immune system. Squalamine works by displacing proteins associated with electrochemical interactions and the cell membrane without causing “obvious structural damage to the cell membrane as measured by changes in permeability” [6]. The displacement of these proteins associated with such chemical interactions and the cytoplasmic membrane is believed to have the potential to effect the “entry, protein synthesis, virion* assembly, virion budding or other steps in the viral replication cycle” [7]. Squalamine has proven to be 85% effective in combating MCMV, EEEV, HBV and HDV in vitro, it has been shown to completely eradicate Dengue fever in vitro and inhibit Yellow Fever by up to 95% in hamsters during in vivo tests. As a result of Squalamine’s effects in humans already having been studied in numerous pre-clinical trials for cancer it has a known safety profile for therapeutic use in humans. However, Squalamine's effectiveness in in vivo in inhibiting viruses is still under investigation as scientists “have not yet optimized Squalamine dosing in any of the animal models [investigated]” [8].
One of the most anticipated of these new broad-spectrum antivirals is LJ001. LJ001 is an incredibly potent antiviral that works by preventing membrane fusion in viruses, essentially allowing LJ001 to inhibit all enveloped viruses provided it is administered prior or during the viral infection. Despite LJ001 also affecting healthy mammalian cells, researchers detail, “it is only the viral membrane whose function appears to be impaired” [9]. The scientists studying LJ001 hypothesize “that this is due to the fact that host membranes are continually remodeled and can repair themselves by metabolizing or extracting membrane-active agents” [10]. LJ001 has proven effective against a range of viral infections including “Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1” [11]. However, unlike other broad-spectrum antivirals pretreatment with LJ001 reduces mortality rates from some of the worlds most serious diseases, including “prevent[ing] virus-induced mortality from Ebola and Rift Valley fever viruses” [12]. However, the lack of specificity in the function of LJ001 it also has its drawbacks, in order to be effective in vivo it would have to be in concentrations too high to be feasible in its current form.
Scientists have made significant advances in the treatment of viral illnesses, discovering (or in some cases even engineering) antivirals effective against a whole spectrum of different viral infections. However, it is important to know that despite this, such developments are still in their infancy. Indeed many of the most promising broad-spectrum antivirals have only just begin in vivo testing and will be unlikely to emerge as potential therapeutic treatments which will be widely available for our own use. Indeed, the lack of specificity among such treatments, which makes them such enticing treatments when compared to specific antivirals, may actually be their downfall. As highlighted by researchers studying LJ001, such a lack of specificity may mean that required concentrations of antivirals for them to be effective would be unfeasible in vivo, a potential obstacle as such antivirals progress towards human trials.
*Virion: An entire virus particle consisting of an outer protein shell called a capsid and an inner core of nucleic acid
[1] Anne Trafton, “New Drug could cure nearly any viral infection”, M.IT. Press Release: http://web.mit.edu/newsoffice/2011/antiviral-0810.html.
[2] [3] Todd H. Rider,* Christina E. Zook, Tara L. Boettcher, Scott T. Wick, Jennifer S. Pancoast, and Benjamin D. Zusman, “Broad-Spectrum Antiviral Therapeutics”, PNAS(2011).
[4] Peter Livermore, “Novel method for apoptosis induction may lead
to development of broad-spectrum antiviral agents”, Future Microbiology.
[5] [6] [7] [8] Michael Zasloff,a,1 A. Paige Adams,b Bernard Beckerman,c Ann Campbell,d Ziying Han,e Erik Luijten,c,f Isaura Meza,g Justin Julander,h Abhijit Mishra,i Wei Qu,c John M. Taylor,e Scott C. Weaver,b and Gerard C. L. WongI, “Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential”, PNAS (2011)
[9][10] Jason A. Wojcechowskyj* and Robert W. Doms, “A Potent, Broad-Spectrum Antiviral Agent that Targets Viral Membranes”, PNAS (2010)
[11] [12] Mike C. Wolf,a Alexander N. Freiberg,b,1 Tinghu Zhang,c,1 Zeynep Akyol-Ataman,a,1 Andrew Grock,a Patrick W. Hong,a Jianrong Li,
d,2 Natalya F. Watson,a Angela Q. Fang,a Hector C. Aguilar,a Matteo Porotto,e Anna N. Honko,f Robert Damoiseaux,g John P. Miller,h Sara E. Woodson,b Steven Chantasirivisal,a Vanessa Fontanes,a Oscar A. Negrete,a Paul Krogstad,h Asim Dasgupta,a Anne Moscona,e Lisa E. Hensley,f Sean P. Whelan,d Kym F. Faull,c Michael R. Holbrook,b Michael E. Jung,c and Benhur Lee, “A broad-spectrum antiviral targeting entry of enveloped viruses”, PNAS (2010)
