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Influenza A virus pandemics still remain a threat to global health. One class of antiviral drugs, namely, inhibitors of the specific viral enzyme neuraminidase, is predominantly used in the fight against these pandemics. These antivirals include zanamivir (Relenza™) and oseltamivir (Tamiflu™). The viral resistance to this class of compounds steadily increases. The M2 proton channel of influenza A virus is an alternative clinically proven target for antiviral therapy. However, many circulating virus strains bear amino acid mutations in the M2 protein, causing resistance to drugs of the adamantane series, M2 blockers, such as rimantadine and amantadine. Consequently, inhibitors targeting mutants of the M2 channel are urgently needed for public biosafety and health. This review is devoted to structural-functional interactions used in practice and mediated by the action of experimental drugs on the protein target, the transmembrane domain of the influenza virus M2 proton channel. An analysis of the experimental and model structural data available in open access is presented.

Fractions of Inonotus obliquus fungus water extract exhibited a virucidal effect towards hepatitis C virus: it 100-fold reduced its infective properties within 10 min. The antiviral effects of fungus extracts manifested after preventive (24 h before infection) and therapeutic use (during infection of porcine embryo kidney cells). Moreover, the data indicate that the birch fungus extracts inhibit production of infective virus by porcine embryo kidney cells.

Based on the substituted derivative of the decahydro- closo -decaborate anion (Ph 4 P) 2 [B 10 H 9 O(CH 2 ) 5 COOH] obtained by opening the tetrahydropyran substituent in the anion [B 10 H 9 O(CH 2 ) 5 ] – , compounds of the general formula Na 2 [B 10 H 9 O(CH 2 ) 6 C(O)X], where X = Trp-OMe ( 1 ), His-OMe ( 2 ), Met-OMe ( 3 ), Pld-OMe ( 4 ), containing various amino acid substituents attached to the pendant carboxyl group, were synthesized. The compounds were isolated as sodium salts. The residues of L-tryptophan (Na 2 1 ) and L-histidine (Na 2 2 ) contained aromatic heterocyclic groups indole and imidazole, respectively, as a side group. In turn, compounds Na 2 3 and Na 2 4 contained substituted alkanes as a side group: L-methionine (Na 2 3 ) contained a methyl ethyl sulfide group, and compound Na 2 4 contained the residue of an aliphatic synthetic amino acid, in which the side group was represented by γ-butyrolactam (2-oxopyrrolidin-3-yl) (Pld-OMe). Compounds Na 2 1 and Na 2 2 were found to exhibit dose-dependent antiviral activity against the influenza virus strain A/IIV-Orenburg/83/2012(H1N1)pdm09 in vitro. IC 50 for compound Na 2 1 was found to be 5.0 μg/mL, and for compound Na 2 2 it was found to be 10.0 μg/mL. Molecular docking of the M2 protein pore and ligands 1 and 2 was performed. It was found that the most probable arrangement of molecules in the pore of the M2 channel is associated with the location of the heterocycle inside the pore of the M2 channel in the region of the residues His37–Trp41, with the arrangement being more favorable for 1 rather than for 2 . This fact explains some difference in the concentrations of suppression of viral reproduction for Na 2 1 and Na 2 2 . For compounds Na 2 3 and Na 2 4 , antiviral activity was not detected.

Here, we prepared a number of quinoline-2-carboxylic acid or quinoxaline-2-carboxylic acid amino acid esters derivatives with aromatic and aliphatic terminal groups (Qln-Ser-OMe, Qln-Thr-OMe, Qox-Thr-OMe, and Qox-Trp-OMe). Compounds were characterized by IR, NMR spectroscopies and MS spectrometry. Silver(I) complexes with the organic ligands of the general form [AgL 2 ]NO 3 were prepared in order to increase their water solubility. The structures of compounds Qox-Trp-OMe and [AgL 2 ]NO 3 (L = Qln-Ser-OMe) were determined by single-crystal X-ray diffraction. The proposed compounds in the form of water-soluble silver(I) nitrate complexes were found to be effective in suppressing the reproduction of the rimantadine-resistant influenza virus strain A/IIV-Orenburg/83/2012(H1N1)pdm09 in experiments in vitro using a MDCK cell culture model.

New amino acid derivatives with carbocycles of adamantine and quinaldic acid were synthesized and their in vitro antiviral activity against influenza A/H5N1 virus was evaluated. Experiments on cultured embryonic porcine kidney epithelial cells showed that amino acid derivatives suppressed viral replication. Tret-butyloxycarbonyl-DL-methionylsulfonyl-1-adamantayl ethylamine and benzyloxycarbonyl-L-trypthophanyl-1-adamantayl ethylamine compounds demonstrated high activity in all in vitro experiments. Moreover, some compounds showed virucidal activity against influenza A/H5N1 virus.

New adamantane derivatives with amino acid residues and other bifunctional compounds were synthesized and their antiviral activity towards influenza A(H1N1)pdm and A(H3N2) viruses was studied. Some of these adamantane derivatives completely suppressed replication of remantadine-resistant influenza A virus strains.

We studied the capacity amino acid derivatives of adamantane to inhibit replication of highly virulent avian influenza A/duck/Novosibirsk/56/05 (H5N1) virus in cultures of swine embryonic kidney cells. Amino acid derivatives of adamantane H-His-Rem and Ad(CH 2 -Ser-OMe) 2 were characterized by lower toxicity than remantadine previously used in the treatment of influenza. Histidine-containing adamantane derivative (H-His-Rem) was the most effective and low-toxic inhibitor of influenza А/H5N1 virus replication and can be recommended for clinical trials to produce a preparation for the treatment and prevention of influenza.

In 1997 we proved that if n is of the form 4 k , 8 k - 1 or 2 2 m + 1 ( 2 k - 1 ) + 3 , where k , m ∈ N , then there are no positive rational numbers x ,  y ,  z satisfying x y z = 1 , x + y + z = n . Recently, N. X. Tho proved the following statement: let a ∈ N be odd and let either n ≡ 0 ( mod 4 ) or n ≡ 7 ( mod 8 ) . Then the system of equations x y z = a , x + y + z = a n . has no solutions in positive rational numbers x ,  y ,  z . A representative example of our result is the following statement: assume that a , n ∈ N are such that at least one of the following conditions holds: n ≡ 0 ( mod 4 ) n ≡ 7 ( mod 8 ) a ≡ 0 ( mod 4 ) a ≡ 0 ( mod 2 ) and n ≡ 3 ( mod 4 ) a 2 n 3 = 2 2 m + 1 ( 2 k - 1 ) + 27 for some k , m ∈ N . Then the system of equations x y z = a , x + y + z = a n . has no solutions in positive rational numbers x ,  y ,  z .

New derivatives of the closo-decaborate anion [B10H9–O(CH2)2O(CH2)3C(O)–L–OCH3]2− (An) (1: L = Trp; 2: L = His; 3: L = Met; 4: L = Ala(2-oxopyrrolidin-3-yl) (Pld) were synthesized and isolated as tetraphenylphosphonium salts (Ph4P)2An. Anions 12−; 22−; 32−, and 42− contain a pendant functional group from the L-tryptophan methyl ester, L-histidine methyl ester, L-methionine methyl ester, or methyl 2-amino-3-(2-oxopyrrolidin-3-yl)propanoate (-Trp–OCH3, -His–OCH3, -Met–OCH3, or -Pld–OCH3) residue, respectively, bonded with the boron cluster anion through the oxybis[(ethane-2,1-diyl)oxy] spacer. This pacer is formed as a result of the nucleophilic opening of the attached dioxane molecule in the [B10H9O(CH2)4O]− starting derivative. Sodium salts of the target compounds were isolated and used in biological experiments. It was established that among compounds Na2An (An = 1–4), not all are capable of inhibiting the cytopathic effect of the virus in vitro. Sodium salts Na2An have a low toxic effect on a monolayer of continuous canine embryonic kidney (MDCK) cell line. Compounds Na21 and Na22 had IC50 of 5.0 and 20.0 μg/mL, respectively, while for compounds Na23 and Na24, IC50 values could not be achieved at the concentrations studied. The studies performed for molecular docking of the anionic part of 12− and 22− with the transmembrane domain of viroporin M2 show some differences in the location of these two ligands inside the M2 canal pore.

The emergence of drug-resistant influenza virus strains necessitates the development of novel antiviral agents with unique mechanisms of action. This study presents the synthesis and in vitro evaluation of a new class of antiviral compounds: sodium salts of amino acid ester conjugates based on the closo-dodecaborate anion [B12H12]2−, linked via a tetrahydropyran-derived spacer (Na2[B12H11O(CH2)6C(O)X], where X = L-Trp-OMe (Na22); L-His-OMe (Na23); L-Met-OMe (Na24); Pld-OMe (Na25)). The antiviral activity was assessed against contemporary, multidrug-resistant influenza A virus strains, including A/Cheboksary/125/2020 (H1N1)pdm09 and A/IIV-Orenburg/83/2012 (H1N1)pdm09. Cross-platform comparison revealed that the dodecaborate-tryptophan conjugate Na22 exhibited comparable efficacy to its lead decaborate analog against the Orenburg strain while demonstrating potent activity (IC50 = 5.0 µg/mL) against the Cheboksary strain with reduced susceptibility to neuraminidase inhibitors (oseltamivir; zanamivir) and complete resistance to M2 channel blockers. The histidine-based conjugate Na23 also showed significant efficacy against the Cheboksary strain, while methionine and lactam derivatives (Na24; Na25) remained inactive. This work confirms boron clusters as versatile platforms for antiviral development and establishes structure–activity relationships crucial for optimizing both B10 and B12-based therapeutics against resistant influenza strains.