Adamantane derivatives as potential inhibitors of p37 major envelope protein and poxvirus reproduction. Design, synthesis and antiviral activity

• Published in: European journal of medicinal chemistry Vol. 221; pp. 113485 - 113496
• Main Authors: Shiryaev, Vadim A., Skomorohov, Michael Yu, Leonova, Marina V., Bormotov, Nikolai I., Serova, Olga A., Shishkina, Larisa N., Agafonov, Alexander P., Maksyutov, Rinat A., Klimochkin, Yuri N.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.10.2021; Elsevier
• Subjects: Adamantane; Adamantane - chemical synthesis; Adamantane - chemistry; Adamantane - pharmacology; Antiviral activity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Life Sciences & Biomedicine; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Microbial Sensitivity Tests; Molecular modelling; Molecular Structure; Orthopox viruses; Pharmacology & Pharmacy; Poxviridae - drug effects; Science & Technology; Structure-Activity Relationship; Viral Envelope Proteins - antagonists & inhibitors; Viral Envelope Proteins - metabolism; Drug design; Molecular modelling; Adamantane; Orthopox viruses; Antiviral activity; VISUALIZATION; ST-246(R); ORTHOPOXVIRUS; VALIDATION; SMALLPOX; MONKEYPOX; FORCE-FIELD; GUI
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113485

Currently, smallpox, caused by the variola virus belonging to the poxvirus family, has been completely eradicated according to the WHO. However, other representatives of poxviruses, such as vaccinia virus, cowpox virus, ectromelia virus, monkeypox virus, mousepox virus and others, remain in the natural environment and can infect both animals and humans. The pathogens of animal diseases, belonging to the category with a high epidemic risk, have already caused several outbreaks among humans, and can, in an unfavorable combination of circumstances, cause not only an epidemic, but also a pandemic. Despite the fact that there are protocols for the treatment of poxvirus infections, the targeted design of new drugs will increase their availability and expand the arsenal of antiviral chemotherapeutic agents. One of the potential targets of poxviruses is the p37 protein, which is a tecovirimat target. This protein is relatively small, has no homologs among proteins of humans and other mammals and is necessary for the replication of viral particles, which makes it attractive target for virtual screening. Using the I-TASSER modelling and molecular dynamics refinement the p37 orthopox virus protein model was obtained and its was confirmed by ramachandran plot analysis and superimposition of the model with the template protein with similar function. A virtual library of adamantane containing compounds was generated and a number of potential inhibitors were chosen from virtual library using molecular docking. Several compounds bearing adamantane moiety were synthesized and their biological activity was tested in vitro on vaccinia, cowpox and mousepox viruses. The new compounds inhibiting vaccinia virus replication with IC50 concentrations between 0.133 and 0.515 μM were found as a result of the research. The applied approach can be useful in the search of new inhibitors of orthopox reproduction. The proposed approach may be suitable for the design of new poxvirus inhibitors containing cage structural moiety. [Display omitted] •A model of poxvirus protein p37 can be used for constructing new drug candidates.•Adamantane containing molecules can effectively break the life cycle of poxviruses.•Polyhedral compounds have considerable potential in poxvirus therapy.