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Research on Substances with Activity Against Orthopoxviruses

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Research on Substances with Activity Against Orthopoxviruses Annals of Agricultural and Environmental Medicine 2013, Vol 20, No 1, 1-7 REVIEW ARTICLE www.aaem.pl Research on substances with activity against orthopoxviruses Marcin Kołodziej1, Justyna Joniec1, Michał Bartoszcze1, Romuald Gryko1, Janusz Kocik2, Józef Knap3 1 Biological Threats Identification and Countermeasure Center, Military Institute of Hygiene and Epidemiology, Puławy, Poland 2 Military Institute of Hygiene and Epidemiology, Warsaw, Poland 3 Department of Epidemiology, Medical University, Warsaw, Poland Kołodziej M, Joniec J, Bartoszcze M, Gryko R, Kocik J, Knap J. Research on substances with activity against orthopoxviruses. Ann Agric Environ Med. 2013; 20(1): 1-7. Abstract Although smallpox was eradicated over 30 years ago, the disease remains a major threat. High mortality, high infectivity and low resistance of the contemporary population make the smallpox virus very attractive to terrorists. The possible presence of illegal stocks of the virus or risk of deliberate genetic modifications cause serious concerns among experts. Hence, it is reasonable to seek effective drugs that could be used in case of smallpox outbreak. This paper reviews studies on compounds with proven in vitro or in vivo antipoxviruses potential, which show various mechanisms of action. Nucleoside analogues, such as cidofovir, can inhibit virus replication. Cidofovir derivatives are developed to improve the bioavailability of the drug. Among the nucleoside analogues under current investigation are: ANO (adenozine N1-oxide) and its derivatives, N-methanocarbothymidine [(N)-MCT], or derivatitives of aciklovir, peninclovir and brivudin. Recently, ST-246 – which effectively inhibits infection by limiting release of progeny virions – has become an object of attention. It has been also been demonstrated that compounds such as: nigericin, aptamers and peptides may have antiviral potential. An interesting strategy to fight infections was presented in experiments aimed at defining the role of individual genes (E3L, K3L or C6L) in the pathogenesis, and looking for their potential blockers. Additionally, among substances considered to be effective in the treatment of smallpox cases, there are factors that can block viral inhibitors of the human complement system, epidermal growth factor inhibitors or immunomodulators. Further studies on compounds with activity against poxviruses are necessary in order to broaden the pool of available means that could be used in the case of a new outbreak of smallpox. Key words Orthopoxvirus, smallpox, antivirals INTRODUCTION leaving the remainder only in the possession of two WHO laboratories: Centers for Disease Control and Prevention in The smallpox virus (VARV – variola virus) is dsDNA virus Atlanta (USA) and (after a transfer in 1994) the Russian State belonging to the Poxviridae family, genus Orthopoxvirus. This Research Center of Virology and Biotechnology (the Vector genus also contains other viruses: vaccinia virus (VACV), Institute) in Novosibirsk [4, 5, 6]. cowpox (CPXV), monkeypox (MPXV), camelpox (CMLV) The cessation of immunization has resulted in lack of and ectromelia virus (ECTV) [1, 2]. Humans are susceptible immunity to smallpox virus in the present population. to the viruses: variola, vaccina, cowpox and monkeypox [3, 4]. This situation raises concerns regarding the possibility of Among all known infectious diseases, smallpox caused purposeful use of smallpox virus as a biological weapon in the greatest number of deaths worldwide [3]. The disease has bioterrorist attacks [6, 7]. It is suspected that there are still two main forms: variola major, with mortality rate reaching illegal stocks of the virus that could be used in the studies 30%, and variola minor, with mortality rate below 5% [1, 3, 5]. on its genetic modifications, which could potentially lead to Variola virus can spread by respiratory droplets or by direct dangerous infections, even in vaccinated individuals [5, 6, 7]. contact. Smallpox is a disease characteristic of humans. There In Poland, the last cases of smallpox occurred in Wrocław, has been no reports on any animal or insect species that Silesia, in 1963, when the disease was diagnosed in 99 people, would serve as reservoirs or vectors of the virus [3]. causing the death of 7 patients. Extensive means of security, In the past, vaccination was the basic method of such as mass vaccination and restrictions on transport prevention and control of smallpox. A mass vaccination of people, were undertaken to prevent the spread of the campaign conducted under the auspices of the World Health epidemic [8]. Organization (WHO) in 1967-1977 made the world free In the USA in 2003, a small epidemic of monkeypox broke of the disease. Eradication of smallpox was announced in out, a disease that may be fatal to humans. This event has 1980, abolishing the need for further vaccination [1]. The shown that monkeypox virus or other animal poxviruses majority of existing smallpox virus stocks were destroyed, are able to break the species barrier and become a human pathogen [4, 9]. Address for correspondence: Marcin Kolodziej, Biological Threats Identification Since none of the anti-smallpox vaccines are regarded and Countermeasure Centre, Military Institute of Hygiene and Epidemiology, Lubelska 2, 24-100 Puławy, Poland entirely safe, seeking new antiviral agents that could protect E-mail: [email protected] people in the case of a natural outbreak of epidemic, or Received: 29 March 2012; accepted: 24 September 2012 deliberate use of smallpox virus, becomes a priority. A pool of 2 Annals of Agricultural and Environmental Medicine 2013, Vol 20, No 1 Marcin Kołodziej, Justyna Joniec, Michał Bartoszcze, Romuald Gryko, Janusz Kocik, Józef Knap. Research on substances with activity against orthopoxviruses drugs with various mechanisms of action may be crucial for Therapeutic potential of cidofovir was also confirmed the rapid and effective response of a national health service by Baker et al. [5]. From 24 known antiviral compounds in case of the emergence of drug-resistant or genetically- they isolated eight: cidofovir (HPMPC), cyclic cidofovir modified virus strains [5, 7]. (cHPMPC), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) In smallpox, symptomatic treatment was usually used, adenine (HPMPA), ribavirin, tiazofurin, carbocyclic and in the case of secondary bacterial infections, antibiotics 3-deazaadenosine, 3-deazaneplanocin A and DFBA (a were administrated. The smallpox vaccine used in the past derivative of adenosine N1-oxide), which inhibited in vitro belongs to the most dangerous vaccines because of the high replication of poxvirus strains VARV-BSH, VARV-YAM, probability of severe complications [6, 9, 10]. Symptoms such VARV-GAR, VACV, CPXV and MPXV. The three most as eczema on vaccinated skin, systemic vaccinia, gangrenous active compounds, cidofovir, cHPMPC and ribavirin, were vaccinia or postvaccinal encephalitis have been reported. also examined for the occurrence of drug resistance in 35 strains of poxviruses from different geographical regions. Cidofovir and other nucleoside analogues. For years, great It was shown that the tested strains have similar sensitivity importance in combating viral infections has been attributed to these drugs without showing resistance to any of them. to nucleoside analogues that can impair viral replication Additionally, cidofovir reduced viral titer in tissues and body [5, 11]. In 2001, the US Food and Drug Administration (FDA) fluids of animals. approved the use of cidofovir (HPMPC – (S)-1-(3-hydroxy- Due to the poor oral bioavailability of cidofovir, its 2-phosphonylmethoxypropyl)cytosine) in the case of a toxicity to kidneys and the occurrence of resistant strains smallpox outbreak [7, 12, 13]. The anti-smallpox activity of [13], the search for analogues lacking these defects is still cidofovir in humans has not been fully described because the continuing [12]. Several ester conjugates of cidofovir with drug appeared after eradication of the disease. However, its lipids, such as hexadecylopropanediol (HDP-HPMPC) and effectiveness has been demonstrated in poxvirus infection in octadecylethanediol (ODE-HPMPC) were tested. They were mice after intravenous, subcutaneous, topical, intranasal (as designed so that they resemble natural lipids absorbed in the spray) and oral (as lipid prodrug) administration [14]. It has small intestine. In contrast to cidofovir, these compounds been confirmed that it is effective against vaccinia, cowpox, penetrate effectively into the blood and cells, yielding a weaker monkeypox, moluscum contagiosum and ecthyma. Cidofovir concentration in the kidneys than HPMPC. Their availability can be administered to people by the intravenous injection after oral administration and lesser nephrotoxicity make of an aqueous solution, but changing the formulation also them useful drugs for the treatment of smallpox [7, 14]. Smee allowed the use of the drug topically in the form of gels or et al. [16] found that HDP-HPMPC given once orally at doses creams, as well as in the form of an aerosol for inhalation 100, 50 and 25 mg/kg protected 80-100% of animals infected or a lipid pro-drug (HDP-HPMPC) for oral administration intranasally with VACV. Lower doses (10 and 5 mg/kg) [14, 15]. Cidofovir is officially registered as a medicine administered for five days protected 30% of animals. HOE961 against CMV retinitis in patients with AIDS. It also shows (diacetate ester prodrug of 2-amino-7-[(1,3-dihydroxy- activity against other viruses: HSV (type
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