If you fight rhinoviruses, the runny nose will pass in a week
Rhinoviruses: in search of the Achilles heelAnna Tyutyunnikova, "Weekly PHARMACY"
It is believed that they are the culprits not only of acute respiratory viral infections (ARVI), but also of more serious diseases, including asthma, as well as allergic reactions in children (Cohen L., Castro M., 2003). This is the reason for the close attention of scientists to these pathogens, because their research can help effectively combat many diseases.
Today, drugs for the prevention and treatment of rhinovirus infections can be divided into four groups: interferons, blockers of cell receptors binding viruses, inhibitors of viral proteases and drugs binding to the protein envelope (capsid) of rhinoviruses.
InterferonsInterferons have long been widely known for their antiviral, anticancer and immunomodulatory effects (Munno I., Marinaro M., 1995; Martin M., 1998).
Currently, several types of recombinant interferons are used to treat various types of viral infections: interferon alpha, interferon alpha-1a, interferon alpha 1b, interferon alpha-2b, interferon beta and interferon gamma (Foser S. et al., 2003; Antonelli G., 2008; Clerico M. et al., 2008). All of them are products of genetic engineering technologies, in which genes encoding interferons are embedded in the genome of bacteria, so that large amounts of pure protein can be produced. Interferons are most often used in the form of intranasal sprays and parenterally.
In the course of studies conducted in the late 80s of the twentieth century, the high effectiveness of recombinant interferon alpha-2b in the prevention of rhinovirus infections was revealed (Hayden F.G. et al., 1986; Hayden F.G., Kaiser D.L., Albrecht J.K., 1998; Sperber S.J., Hayden F.G., 1988). Thus, with intranasal use, its ability to prevent the incidence of rhinovirus infection was noted, but pronounced antiviral activity after infection was not detected (Hayden F.G. et al., 1986; Sperber S.J., Hayden F.G., 1988). Thus, interferons are used as highly effective preventive agents, but drugs are needed that can not only prevent, but also treat rhinovirus infection.
Blockers of cellular receptors binding rhinovirusesMore than 90% of rhinoviruses use intercellular adhesion molecules (ICAM) as a binding receptor (Turner R.B., 2001).
In this way, viruses penetrate into sensitive cells, where they cause diseases. Scientists are paying close attention to this mechanism, because understanding it will allow us to develop drugs that can block the interaction of the virus with ICAM and, accordingly, stop or even prevent the disease.
In 1999, the German company Boehringer Ingelheim began developing a drug called Tremacamra. This drug blocked ICAM receptors, but its effectiveness was quite low; moreover, to get the effect, it had to be used 6 times a day (intranasally), and the treatment itself should be started in the first 12 hours after infection. However, despite the fact that Tremacamra research has been suspended, scientists continue to research in this direction, since it seems very promising. So, in January 2009, an article was published in the journal "Antiviral Research" on the newly developed drug levocetirizine, which has pronounced antiviral properties, blocking the production of ICAM, as well as preventing the release of interleukins (IL)-6 and IL-8 and the synthesis of nuclear factor molecules NF-kB. Levocetirizine was tested on cultures of cells infected with rhinovirus, where it demonstrated the ability to block virus replication (Jang Y.J., Wang J.Y., Kim J.S. et al., 2009).
Protease inhibitorsIt is known that rhinoviruses contain a single-stranded RNA molecule encoding a polyprotein, which must be cut into fragments before it can perform its functions.
This cutting is performed by special enzymes ― proteases, one of which, C3-protease, is considered as a target for antiviral drugs. The drug rupinrivir was developed, which in vitro studies showed high efficacy against all studied strains of rhinoviruses, clinical isolates of rhinoviruses, as well as enteroviruses. A DNA analysis was carried out, according to which there is a conservative region in the genome of the virus, namely in the gene encoding the C3 protease, with which this drug can bind. Unfortunately, during clinical studies, the antiviral activity of rupinrivir was not detected, however, another C3 protease inhibitor was found, which demonstrated antiviral activity against more than 80% of rhinovirus serotypes. Currently, trials of this drug are continuing (Dragovich P.S., Prins T.J., Zhou R. et al., 1999, Mattews D.A. et al., 1999).
Drugs that bind to the capsidOn the surface of the viral capsid there are specific regions responsible for binding the virus to the receptor and performing other functions.
One of the important regions is the so―called canyon formed by capsid elements having the names VP1 and VP3. Currently, drugs are being developed that can bind to this region, blocking the attachment of the viral particle to the receptor, as well as preventing the "undressing" of the virus (destruction of the capsid and the release of nucleic acid) upon penetration into the cell. Laboratory studies have shown that almost all developed drugs capable of binding to the capsid are effective in vitro.
One of the first such drugs was disoxaril, developed by Sterling Winthrop Pharmaceuticals. According to preclinical studies in mice, it is effective against rhinoviruses, enteroviruses and polioviruses (Diana G.D. et al., 1985; Otto M.J. et al., 1985), however, clinical studies with volunteers have not been successful ― the drug showed extremely low efficacy, although it was later revealed that the modified disoxaril is able to prevent the development of colds when used for preventive purposes (Rotbart H.A., 2002).
The next drug binding to the capsid was pleconaril (picovir). During its clinical trials, it was found to be quite effective against picornavirus infection (rhinoviruses belong to the picornavirus family). However, a number of side effects were also noted – in particular, patients had a mild digestive disorder, and women who took oral hormonal contraceptives simultaneously with pleconaril had various menstrual cycle disorders (Hayden F.G. et al., 2002; 2003). In addition, when using the drug, the number of viruses resistant to it increased. Therefore, in March 2002, the Antiviral Drugs Advisory Committee under the U.S. Food and Drug Administration recommended against using pleconaril as a drug for the treatment of rhinovirus infections.
The next drug that has the property of binding to the capsid was pyrodavir, developed by the Janssen Research Foundation. According to clinical trials, the drug shows pronounced antiviral activity when used 6 times a day; already when used 3 times a day, it is not noted.
In November 2008, the journal "Bioorganic&Medicinal Chemistry" published a paper by Chinese scientists from the Beijing Institute of Pharmacology and Toxicology (Beijing Institute of Pharmacology and Toxicology), dedicated to the synthesis and testing of a drug called chloropyridazine. Various chloropyridazine derivatives have demonstrated a pronounced ability to bind to the capsid and, accordingly, antiviral activity, so the researchers intend to continue studying the drug (Shi-Yong Fan et al., 2008).
Thus, research in this direction seems very promising. It is possible to develop drugs that would bind to the capsid effectively enough, showing antiviral activity not only in vitro, but also in vivo. However, there are certain problems, in particular, the uniqueness of some regions on the surface of the capsid of viruses of different serotypes. Therefore, scientists face the need to develop such drugs that would be effective against specific serotypes and types of rhinoviruses.
And although today more than 100 serotypes of rhinoviruses have been identified (which are usually divided into 2 groups ― human rhinovirus type A (HRV A) and human rhinovirus type B (HRV B)), modern methods of their analysis are considered ineffective because they use antibodies against known serotypes, while infectious diseases can also cause serotypes unknown; accordingly, it is almost impossible to identify them using traditional methods. That is why the primary task is to study the genome structure of new serotypes of rhinoviruses, because thanks to this it is possible not only to find new types of viruses, but also to understand which unique sequences are in the genome, which specific proteins synthesize viruses, and this is the first step to create drugs against these pathogens.
In 2007, a group of scientists from the University of Wisconsin investigated rhinoviruses that cause diseases of the respiratory system with various symptoms. The researchers suggested that the use of molecular diagnostic methods (polymerase chain reaction, genome sequencing and phylogenetic analysis) developed for viruses of other families may be more effective than the use of traditional methods. Using molecular methods, the authors showed that there are much more serotypes of rhinoviruses circulating in the environment than is known; moreover, all the viruses isolated de novo (that is, for the first time) are not cultured on standard nutrient media, and the authors suggested that this is why they have not yet been detected.
The work of this group of researchers was continued by Peter McErlean and colleagues, who analyzed several serotypes of rhinoviruses previously declared as belonging to the species HRV A, comparing their nucleotide sequences with the genomes of known species: HRV A, HRV B, HEV (human enterovirus) and two animal enteroviruses. In addition, the authors created a three-dimensional computer model of the capsid of the studied viruses in order to find unique regions on its surface that would help classify these viruses. As a result, among the serotypes studied, a virus was found with such specific characteristics (less than 50% correspondence of its nucleotide sequence to the genomes of other rhinoviruses and enteroviruses, specific regions on the surface of the capsid) that it was decided to assign it to a new species called HRV C (McErlean P., Shackelton L. et al., 2008).
In January 2009, data also appeared in the journal "Science" that another type of rhinoviruses, which belong to the type HRV D, was detected using the molecular genetic methods described above (Palmenberg A.C., Spiro D., Kuzmickas R. et al, 2009).
Thus, today research in the development of antiviral drugs continues, and molecular genetic methods can help to obtain new information about rhinoviruses, which can later be used to develop drugs against these pathogens.
Portal "Eternal youth" www.vechnayamolodost.ru16.03.2009