Abstracts summarizing recent research overseen by the WHO Advisory Committee on Variola Virus Research - 2003
Update on search for antivirals against human-pathogenic orthopoxviruses
E.F.Belanov, N.I.Bormotov, O.A.Serova, S.M.Balakhnin, A.E.Nesterov, I.A.Ryazankin, S.K.Kotovskaya, M.K.Kukhanova, E.A.Shirokova, M.V.Yaz’ko, A.G.Pokrovsky, V.N.Charushin, O.N.Chupakhin, L.S.Sandakhchiev.
State Research Center of Virology and Biotechnology Vector, Koltsovo, Novosibirsk oblast, 630559 Russia
Please direct all queries to the authors at the addresses given.
Under the ISTC Project 1989p/BTEP23, SRC VB VECTOR conducts a search for new chemical compounds with a therapeutic and prophylactic potential. This work was approved by WHO and the project was also coordinated with and approved by the Russian Ministry of Health and the Russian Ministry of Industry, Science and Technologies.
The antiviral search effort involves the use of vaccinia virus (strain L-IVP), cowpox virus (strain GRI-90), and four strains of variola virus (Ind-3a, 6-58, Congo-9, Butler). In addition to the above-mentioned variola virus strains, the most promising compounds were tested using additional variola virus strains (Wsim Ahmed, Aslam, Helder, M-N-60, M-Bl-60, Mary, Ngami, Taj Barin, M-A-60, 22/62).
Compounds for the testing of antiviral activity are synthesized by the Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences (Novosibirsk), Ural Polytechnic University (Ekaterinburg), and Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences (Moscow). These teams are the well-know leaders in the synthesis of a wide range of compounds antiviral research purposes.
The strategy of search for compounds with antiviral activity is based on testing the degree of inhibition of reproduction of different orthopoxviruses in cell culture, in the presence of compounds under study. More than 4300 compounds have been synthesized and tested to date.
The primary screening performed on different strains of variola virus demonstrated that different strains varied in their susceptibility to one and the same compound. However, this variation is far less than variation revealed with regard to different representatives of orthopoxviruses.
Monkeypox virus turned out to be most susceptible and cowpox virus - least susceptible. According to our findings, the susceptibility of variola virus lies somewhere between these two, and perhaps closer that of monkeypox virus.
From more than 4300 compounds tested, several lead compounds were identified to be used in further studies, in experiments involving animal models. We were able to discover several new classes of antiviral compounds, in particular derivatives of benzotriazines and 1,2,4-triazines.
Moreover, a number of compounds were synthesized for which antiviral activity was demonstrated for vaccinia virus. This current study pioneered in the testing of their activity with regard to variola, monkeypox, and cowpox viruses.
New derivatives of N-oxyadenosine, noraristeromycin, hydroxycytidine and several other compounds have been synthesized and their antiviral activity has been demonstrated. Compounds with antiviral activity that have been discovered require further studies in order to verify their activity in appropriate laboratory models of smallpox and conduct preclinical and clinical trials on these.