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.

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.