Prospects for the use of macrocyclic photosensitizers for inactivation of SARS-CoV-2: selection of compounds leaders based on the molecular docking data.

The treatment of coronavirus COVID-19, like other viral diseases, is currently underdeveloped. This fact necessitates the search for new drugs and treatment methods that will effectively disrupt the life cycle of the virus. A big problem in the therapy of viral diseases is the ability of viruses to evade the host's immune response. We suppose that the search for drugs that can change the evasiveness of the virus from the immune response of the host is a very promising strategy, as it can help the body to cope with the infection. Protein SARS-CoV-2 ORF8 is one of the key proteins that can suppress antiviral immunity. This paper considers the available information on the structure and functioning of ORF8, as well as the results of molecular docking of ORF8 to a wide range of tetrapyrrole macroheterocyclic compounds capable of generating reactive oxygen species upon photoirradiation. This principle of photoinactivation of biosubstrates underlies the methods of photodynamic therapy of cancer. Application of photoinactivation of drug-resistant forms of bacteria and some viruses can be useful in the fight against COVID-19 and other viral infections. In this work, the structure of ORF8 complexes with macrocyclic compounds is considered in detail, the dependence of their binding affinity on the nature of macrocycles and the nature of peripheral substituents is analyzed and spectral studies of the binding of ORF8 to chlorin is performed. This paper is a part of a large project to investigate the possibility of using macrocyclic compounds for the treatment of viral diseases.Communicated by Ramaswamy H. Sarma.

Destruction of Chitosan and Its Complexes with Cobalt(II) and Copper(II) Tetrasulphophthalocyanines.

Chitosan is a naturally occurring polysaccharide derived from chitin with a wide range of uses. Phthalocyanines are macroheterocyclic compounds that have a number of useful properties such as coloring and catalytic and antioxidant activity. Phthalocyanines are able to immobilize on chitosan, forming complexes with new useful properties. In this work, we evaluated the ability of phthalocyanines to increase the thermal stability of chitosan. Chitosan (CS) forms complexes with copper(II)-(CuPc) and cobalt(II)-(CoPc) tetrasulphophthalocyanines. The processes of destruction of chitosan (CS) and its complexes with sulphophthalocyanines CuPc and CoPc in oxidizing and inert atmospheres have been studied. It was established that, regardless of the atmosphere composition, the first chemical reactions taking place in the studied systems are elimination reactions. The latter ones in the case of chitosan and complex CS-CuPc lead to the formation of spatially crosslinked polymer structures, and it causes the release of CuPc from the polymer complex. It was found that in the case of CS-CoPc elimination reactions did not lead to the formation of crosslinked polymer structures but caused the destruction of the pyranose rings with a partial release of CoPc. Metallophthalocyanines showed antioxidant properties in the composition of complexes with chitosan, increasing the temperature of the beginning of glycosidic bond cleavage reaction by 30-35 °C in comparison with the similar characteristics for chitosan.

Possible therapeutic targets and promising drugs based on unsymmetrical hetaryl-substituted porphyrins to combat SARS-CoV-2.

Coronavirus disease 2019 is a serious disease that causes acute respiratory syndrome and negatively affects the central nervous system. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) crosses the blood-brain barrier due to the spike (S) protein on the surface of the viral particles. Thus, it is important to develop compounds that not only have an inhibitory effect but are also capable of completely deactivating the S protein function. This study describes the purposeful modification of porphyrins and proposes compounds, asymmetrically hetaryl-substituted porphyrins with benzothiazole, benzoxazole, and N-methylbenzimidazole residues, to deactivate the S protein functions. Molecular docking of SARS-CoV-2 proteins with hetaryl-substituted porphyrins showed that the viral S protein, nucleocapsid (N) protein, and non-structural protein 13 (nsp13) exhibited the highest binding affinity. Hetaryl-substituted porphyrins form strong complexes (13-14 kcal/mol) with the receptor-binding domain of the S protein, while the distance from the porphyrins to the receptor-binding motif (RBM) does not exceed 20 Å; therefore, RBM can be oxidized by 1O2, which is generated by porphyrin. Hetaryl-substituted porphyrins interact with the N protein in the serine/arginine-rich region, and a number of vulnerable amino acid residues are located in the photooxidation zone. This damage complicates the packaging of viral RNA into new virions. High-energy binding of hetaryl-substituted porphyrins with the N- and C-terminal domains of nsp13 was observed. This binding blocks the action of nsp13 as an enzyme of exoribonuclease and methyltransferase, thereby preventing RNA replication and processing. A procedure for the synthesis of hetaryl-substituted porphyrins was developed, new compounds were obtained, their structures were identified, and their photocatalytic properties were studied.

Molecular mechanisms causing albumin aggregation. The main role of the porphyrins of the blood group.

In this paper was studied the interaction of deutero- and hematoporphyrin with bovine serum albumin, using various methods of physico-chemical analysis. It was established that the localization of porphyrins occurred in the IB subdomain, while hematoporphyrin interacted with the protein in a monomeric form, and deuteroporphyrin - as a J-dimer. Based on spectral studies, the affinity constants of binding albumin with porphyrins were determined, and the affinity of the protein for deuteroporphyrin appeared to be higher than for hematoporphyrin. It was shown that the interaction of albumin with the studied porphyrins led to a change in the secondary structure of the protein, it being accompanied by a decrease in the proportion of disordered protein fragments and an increase in ß-folding.

Thermochemical research of chitosan complexes with sulfonated metallophthalocyanines.

The complexation processes of chitosan with cobalt(II)tetrasulfophthalocyanine (CoPc) and copper(II)tetrasulfophthalocyanine (CuPc) were studied calorimetrically in solution. It was established that CoPc forms two types of complexes with chitosan, while CuPc forms a single type of complex with chitosan, in which copper(II)tetrasulfophthalocyanine is in dimerized form. The complexes are thermodynamically stable, which was allowed to study them in a solid form by different methods. Joint application of DSC and TG/DTG methods allowed us to identify the temperature intervals for evaporation of physically and chemically bounded water and thermal decomposition of chitosan and its complexes. The glass transition temperature of chitosan (110.8 °C) is greater than the glass transition temperature of the complexes with CuPc (74.7 °C) and CoPc (71.2 °C). Using SEM images and X-ray data of heated, unheated chitosan and its complexes, it was shown that the complexes are predominantly amorphous. Heating of chitosan and its leads to increasing of amorphous phase. Modification of chitosan by phthalocyanines leads to decreasing of thermal stability of complexes insignificantly.

Spectral and thermochemical research of the DNA polyplex with chitosan formation process and the influence of anionic and cationic compounds.

In this paper, the results of a spectral and thermochemical study of the DNA polyplex formation with chitosan and the effect of ethidium bromide polyplexes, sodium dodecyl sulfate, n-octyltrimethyl ammonium bromide, poly(4-styrenesulfonic acid), and heparin on the stability of the complexes are considered. It has been established that chitosan forms thermodynamically stable complexes with ethidium bromide (EtBr), in which there exists one monomer unit of chitosan for two ethidium bromide ones. The interaction of ethidium bromide with chitosan leads to a charge exchange of the polymer surface. The impact of chitosan on the intercalated DNA-EtBr complex conditions a release of EtBr with a polyplex formation. The process of polyplex formation in the presence of ethidium bromide proceeds endothermically, and in its absence the reaction is exothermic. The polyplex particles formed from DNA after release of EtBr are larger and have a smaller charge, as compared to the polyplex particles obtained without ethidium bromide. It has been found that anionic compounds cause the degradation of polyplexes, and it can prove to be a significant obstacle for using chitosan polyplexes in transfection, since in the presence of heparin in the bloodstream, the complexes will break down before reaching the target.

Interactions of tetracationic porphyrins with DNA and their effects on DNA cleavage.

The interaction of tetracationic porphyrins with DNA was studied using UV-Vis absorption, fluorescence spectroscopy and viscometry, and the particle sizes were determined. Аs cationic porphyrins, two isomer porphyrins, 3,3',3″,3‴-(5,10,15,20-Porphyrintetrayl)tetrakis(1-methylpyridinium) (TMPyP3) and 4,4',4″,4‴-(5,10,15,20-Porphyrintetrayl)tetrakis(1-methylpyridinium) (TMPyP4), were studied. They differ in the position of NCH3+ group in phenyl ring of the porphyrins and hence, in degree of freedom of rotation of the phenyl rings about the central macrocycle. It was found that intercalated complexes are formed at DNA/porphyrin molar ratios (R) of 2.2 and 3.9 for TMPyP3 и TMPyP4, respectively. Decreasing R up to 0.4 and 0.8 for TMPyP3 и TMPyP4, respectively, leads mainly to formation of outside complexes due to π-π stacking between the porphyrin chromophores interacting electrostatically with phosphate framework of DNA. Each type of the obtained complexes was characterized using Scatchard approach. It was ascertained that the affinity of TMPyP4 to DNA is stronger than TMPyP3, meanwhile the wedge effect of the latter is higher. The differences between the porphyrin isomers become more evident at irradiation of their complexes with DNA. It was established that irradiation of the intercalated complexes results in DNA fragmentation. In the case of TMPyP4, DNA fragments of different size are formed. The irradiation of the outside DNA/porphyrin complexes leads to cleavage of DNA (TMPyP3 and TMPyP4) and partial destruction of the complex due to photolysis of the porphyrin (TMPyP3).

First tellurium-containing phthalocyanine analogues: strong effect of tellurium on spectral, redox and conductivity properties of porphyrazines with annulated chalcogenodiazole ring(s).

The first tellurium-containing phthalocyanine analogues have been prepared and spectroscopically characterised: the Mg(II) complex of tetra(1,2,5-telluradiazolo)porphyrazine and a low-symmetry tert-butyl substituted Mg(II) tribenzoporphyrazine with one fused 1,2,5-telluradiazole ring. It was observed that the introduction of Te atom(s) reduces the energy of the Q-transition, facilitates the reduction of the macrocycle and strongly increases the conductivity of thin films.