**3. Pathogenic Targets of Influenza Viruses in Humans**

Cells of the single-layer multi-row cylindrical ciliated epithelium of the respiratory tract are main targets of the influenza virus. For infection, the virus must overcome the factors of non-specific resistance of the organism such as the viscous properties of mucus, the movement of the cilia of the cylindrical epithelium, action of non-specific inhibitors of viral replication in mucus, the macrophagal barrier and IgA [30]. With the help of HA, the virus attaches to the receptors of target cells and penetrates them, where the replication cycle takes place [5]. After 4–6 h, a batch of new viruses appears in the cell and then they are pushed out through the cell membrane to the outside. After 24 h, the number of viruses whose "parent" entered the cell can reach several hundred million. The released virions infect neighboring cells and some of them enter in the blood. The subsequent death of epithelial cells is caused not only by the cytopathogenic effect of the virus but also by the inability of the cell to fully recover after the replication of the pathogen. In the early stages of infection, Toll-like receptors (TLR) are involved in the recognition of conservative molecules characteristic of pathogenic microorganisms. The influenza virus stimulates the TLR responses of innate and adaptive immunity [31]. On the cell membrane, TLR4 and C-type lectin receptors (MMR-mannose and MGL-galactose) interact with the glycoproteins of the viral membrane, HA, and NA [32]. Inside cells, the endosomal receptors TLR3, TLR7, TLR10, and cytoplasmic RIG1 respond to viral RNA and RNP [33,34].

Since this article summarizes obtaining experimental data on potential next generation of anti-viral agents: biopolymers from brown, red, and green algae, the above-discussed information concerning virus action is important for understanding of mechanisms of the action of marine sulphated polysaccharides on the influenza virus and its targets in the body.

#### **4. Recent Anti-Influenza Drugs**

Despite the use of a significant number of anti-influenza drugs in medicine of different countries, the search for and development of new, effective and whenever possible harmless drugs continue [35,36]. Currently, for the prevention and treatment of influenza infection, a number of drugs are available with different mechanisms of action, such as limiting the infection at the early stages, stimulating innate immunity, and manipulating the effect of interferons (Table 1).

For a long time, rimantadine and amantadine were very actively used to treat the flu. Leibbrand et al. [37] reported that these anti-influenza drugs act on two stages of the life cycle of the influenza virus: stripping the virus and releasing virus particles from the cell after replication. Rimantadine is able to increase the acidity inside vacuoles surrounding viral particles after they penetrate into the cell. As a result, the fusion of the influenza virus with the vacuole membrane is prevented, which makes it impossible to transfer viral genetic material from the virus particle to the cytoplasm of the cell. Thus, rimantadine becomes an obstacle between the influenza virus and the genome of the host. Along with clinical efficacy, these drugs caused side effects in the gastrointestinal tract and the nervous system [38]. In addition, many influenza A viruses (for example, H3N2, H1N1) quickly became resistant to these agents [39].



At present, adamantane group of drugs are recommended in case all other measures fail. In the last decade, a number of drugs with direct action on the influenza virus (direct-acting antivirals, DAA) have appeared [39]. These include NA inhibitors (oseltamivir/TamifluTM and undecivir/RelenzaTM), M2 channel blockers, and fusion inhibitors (umifenovir/ArbidolTM). Zanamivir and oseltamivir have shown lower than expected efficacy in clinical trials. At the same time, these drugs are more effective in children, in whom the drugs reduce the duration of the disease if they are applied within 48 h after the onset of the first symptoms; they also reduce the number of serious complications. Moreover, these drugs are successfully used to prevent and reduce the intensity of symptoms of seasonal flu. The disadvantages of these chemotherapy drugs are a decrease in their effectiveness during the later stages of infection [40]. In cases of prolonged, complicated flu, pathogenic therapy preparations are used to eliminate the effects of the cytokine storm, reducing the severity of reactive processes [15]. Such processes are induced by the virus, but are carried out by the host mechanisms. These include toxic shock syndrome, hyperproduction of proinflammatory cytokines, cellular tissue infiltration, haemorrhagic syndrome, etc. Although modern drugs are quite effective against currently circulating influenza virus strains, their use often leads to the selection of resistant viruses and resistant strains [11].

In this regard, we need new therapeutic approaches and broad-spectrum drugs. Drugs aimed at various viruses or impairing different stages of influenza virus replication will represent a serious means of fighting infections and minimizing the development of resistant viruses. The sulphated polysaccharides of algae (red, brown and green), such as carrageenans, fucoidans, and ulvans, have been studied as anti-influenza drugs and met these requirements. At the same time, there are other compounds from algae that also have antiviral effects, including anti-influenza action, which should be subjected to further experimental and clinical study.

#### **5. Polysaccharides**

These compounds represent a class of biopolymers, the content and structure of which vary depending on the type of algae, its place of growth, climatic conditions, harvest season, method of extraction and many other factors [41]. According to the literature, sulphated polysaccharides (fucoidans, galactofucans, dextran sulphates, carrageenans, sulphated chitosans, synthetic polyvinyl, and polyethylene sulphates) have antiviral activity not only against the influenza virus but also against many other viruses, such as those that cause hepatitis C, tick-borne encephalitis, haemorrhagic fever with renal syndrome, dengue fever, and AIDS. It is known that, in the human body, the most prevalent heteropolysaccharides are glycosaminoglycans, negatively charged long unbranched polysaccharides consisting of disaccharides repeating units [42]. The binding of glycosamines with different ligands leads to post-translational modifications that facilitate cell migration, proliferation, and differentiation. The glycosaminoglycans, a class of heparan/heparan sulphates present in the basement membrane, in the extracellular matrix, and on the cell surface that are able to specifically interact with macromolecules of the extracellular matrix (fibronectin and laminin), enzymes, and an extensive class of heparan-binding molecules (growth factors and chemokines) [42]. Mimetics of glycosaminoglycan, including heparan/heparan sulphates provide a wide range of biological effects and modulate the effect of many signaling molecules in cells [43]. Sulphated polysaccharides of algae are natural mimics of heparan sulphates. Fucoidans and carrageenans can mimic the action of endogenous factors and regulate the functions of microorganism systems through key cell and enzyme receptors. Due to this, sulphated polysaccharides have the ability to bind to various receptors on the surface of the host cell and compete with viruses for glycoprotein receptors [44].

One of the characteristic features of algal polysaccharides is the presence of sulphate groups and uronic acid residues in their structures, which distinguishes them from the polysaccharides of land plants [45]. In the last decade, quite a lot of scientific articles have appeared that presents the effectiveness of fucoidans and carrageenans in influenza infection, as well as acute viral "colds".
