Drug Development against Smallpox: Present and Future

Déborah Delaune, Frédéric Iseni, Déborah Delaune, Frédéric Iseni

Abstract

Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus de novo, implying that VARV could, in theory, be resurrected. Because of this new perspective, the WHO Advisory Committee on VARV Research released new recommendations concerning research on poxviruses that strongly encourages pursuing the development of new antiviral drugs against orthopoxviruses. In 2018, the U.S. FDA advised in favor of two molecules for smallpox treatment, tecovirimat and brincidofovir. This review highlights the difficulties to develop new drugs targeting an eradicated disease, especially as it requires working under the FDA "animal efficacy rule" with the few, and imperfect, animal models available.

Keywords: FDA animal rule; antiviral; smallpox.

Copyright © 2020 American Society for Microbiology.

References

    1. Fenner F. 1977. The eradication of smallpox. Prog Med Virol 23:1–21.
    1. Wade N. 1978. New smallpox case seems lab-caused. Science 201:893. doi:10.1126/science.684414.
    1. World Health Assembly. 1980. Resolution of the World Health Assembly: declaration of global eradication of smallpox. World Health Organization, Geneva, Switzerland: .
    1. Rotz LD, Khan AS, Lillibridge SR, Ostroff SM, Hughes JM. 2002. Public health assessment of potential biological terrorism agents. Emerg Infect Dis 8:225–230. doi:10.3201/eid0802.010164.
    1. WHO. 2015. The Independent Advisory Group on Public Health Implications of Synthetic Biology Technology Related to Smallpox. World Health Organization, Geneva, Switzerland: .
    1. Noyce RS, Lederman S, Evans DH. 2018. Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments. PLoS One 13:e0188453. doi:10.1371/journal.pone.0188453.
    1. Kern ER. 2003. In vitro activity of potential anti-poxvirus agents. Antiviral Res 57:35–40. doi:10.1016/s0166-3542(02)00198-5.
    1. Food, Drug Administration HHS. 2002. New drug and biological drug products; evidence needed to demonstrate effectiveness of new drugs when human efficacy studies are not ethical or feasible. Final rule. Fed Regist 67:37988–37998.
    1. Allio T. 2018. The FDA Animal Rule and its role in protecting human safety. Expert Opin Drug Saf 17:971–973. doi:10.1080/14740338.2018.1518429.
    1. FDA. 2015. Product development under the animal rule: guidance for industry. U.S. Food and Drug Administration (FDA), Silver Spring, MD: .
    1. Costantino V, Kunasekaran MP, Chughtai AA, MacIntyre CR. 2018. How valid are assumptions about re-emerging smallpox? A systematic review of parameters used in smallpox mathematical models. Mil Med 183:e200–e207. doi:10.1093/milmed/usx092.
    1. Breman JG, Henderson DA. 2002. Diagnosis and management of smallpox. N Engl J Med 346:1300–1308. doi:10.1056/NEJMra020025.
    1. Fenner FH, Arita I, Jezek Z, Ladnyi ID. 1988. Smallpox and its eradication. World Health Organization, Geneva, Switzerland.
    1. Councilman WT, Magrath GB, Brinckerhoff WR. 1904. The pathological anatomy and histology of variola. J Med Res 11:12–135.
    1. Hahon N, Wilson BJ. 1960. Pathogenesis of variola in Macaca irus monkeys. Am J Hyg 71:69–80. doi:10.1093/oxfordjournals.aje.a120091.
    1. Hahon N, Mc GM. 1961. Air-borne infectivity of the variola-vaccinia group of poxviruses for the cynomolgus monkey, Macaca irus. J Infect Dis 109:294–298. doi:10.1093/infdis/109.3.294.
    1. Jahrling PB, Hensley LE, Martinez MJ, Leduc JW, Rubins KH, Relman DA, Huggins JW. 2004. Exploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpox. Proc Natl Acad Sci U S A 101:15196–15200. doi:10.1073/pnas.0405954101.
    1. Gubser C, Hue S, Kellam P, Smith GL. 2004. Poxvirus genomes: a phylogenetic analysis. J Gen Virol 85:105–117. doi:10.1099/vir.0.19565-0.
    1. Brown K, Leggat PA. 2016. Human monkeypox: current state of knowledge and implications for the future. Trop Med Infect Dis 1:E8. doi:10.3390/tropicalmed1010008.
    1. Mucker EM, Chapman J, Huzella LM, Huggins JW, Shamblin J, Robinson CG, Hensley LE. 2015. Susceptibility of marmosets (Callithrix jacchus) to monkeypox virus: a low dose prospective model for monkeypox and smallpox disease. PLoS One 10:e0131742. doi:10.1371/journal.pone.0131742.
    1. Baxby D, Bennett M, Getty B. 1994. Human cowpox 1969–93: a review based on 54 cases. Br J Dermatol 131:598–607. doi:10.1111/j.1365-2133.1994.tb04969.x.
    1. Essbauer S, Pfeffer M, Meyer H. 2010. Zoonotic poxviruses. Vet Microbiol 140:229–236. doi:10.1016/j.vetmic.2009.08.026.
    1. Mauldin MR, Antwerpen M, Emerson GL, Li Y, Zoeller G, Carroll DS, Meyer H, Mauldin M, Antwerpen M, Emerson G, Li Y, Zoeller G, Carroll D, Meyer H. 2017. Cowpox virus: what's in a name? Viruses 9:101. doi:10.3390/v9050101.
    1. Kramski M, Matz-Rensing K, Stahl-Hennig C, Kaup FJ, Nitsche A, Pauli G, Ellerbrok H. 2010. A novel highly reproducible and lethal nonhuman primate model for orthopox virus infection. PLoS One 5:e10412. doi:10.1371/journal.pone.0010412.
    1. Smith AL, St Claire M, Yellayi S, Bollinger L, Jahrling PB, Paragas J, Blaney JE, Johnson RF. 2012. Intrabronchial inoculation of cynomolgus macaques with cowpox virus. J Gen Virol 93:159–164. doi:10.1099/vir.0.036905-0.
    1. Titova KA, Sergeev AA, Zamedyanskaya AS, Galahova DO, Kabanov AS, Morozova AA, Bulychev LE, Sergeev AA, Glotova TI, Shishkina LN, Taranov OS, Omigov VV, Zavjalov EL, Agafonov AP, Sergeev AN. 2015. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy. J Gen Virol 96:2832–2843. doi:10.1099/vir.0.000216.
    1. Earl PL, Americo JL, Moss B. 2012. Lethal monkeypox virus infection of CAST/EiJ mice is associated with a deficient gamma interferon response. J Virol 86:9105–9112. doi:10.1128/JVI.00162-12.
    1. Gallardo-Romero NF, Hutson CL, Carroll D, Kondas AV, Salzer JS, Dietz-Ostergaard S, Smith S, Hudson P, Olson V, Damon I. 2020. Use of live Variola virus to determine whether CAST/EiJ mice are a suitable surrogate animal model for human smallpox. Virus Res 275:197772. doi:10.1016/j.virusres.2019.197772.
    1. Bray M, Martinez M, Smee DF, Kefauver D, Thompson E, Huggins JW. 2000. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis 181:10–19. doi:10.1086/315190.
    1. Oliveira JSD, Figueiredo PDO, Costa GB, Assis FLD, Drumond BP, da Fonseca FG, Nogueira ML, Kroon EG, Trindade GDS, Oliveira J, Figueiredo P, Costa G, Assis F, Drumond B, da Fonseca F, Nogueira M, Kroon E, Trindade G. 2017. Vaccinia virus natural infections in Brazil: the good, the bad, and the ugly. Viruses 9:340. doi:10.3390/v9110340.
    1. Smee DF, Bailey KW, Wong MH, Sidwell RW. 2001. Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res 52:55–62. doi:10.1016/s0166-3542(01)00159-0.
    1. Smee DF, Dagley A, Downs B, Hagloch J, Tarbet EB. 2015. Enhanced efficacy of cidofovir combined with vaccinia immune globulin in treating progressive cutaneous vaccinia virus infections in immunosuppressed hairless mice. Antimicrob Agents Chemother 59:520–526. doi:10.1128/AAC.04289-14.
    1. Parker S, Siddiqui AM, Painter G, Schriewer J, Buller RM. 2010. Ectromelia virus infections of mice as a model to support the licensure of anti-orthopoxvirus therapeutics. Viruses 2:1918–1932. doi:10.3390/v2091918.
    1. Parker S, Siddiqui AM, Oberle C, Hembrador E, Lanier R, Painter G, Robertson A, Buller RM. 2009. Mousepox in the C57BL/6 strain provides an improved model for evaluating anti-poxvirus therapies. Virology 385:11–21. doi:10.1016/j.virol.2008.11.015.
    1. Greene H. 1933. A pandemic of rabbit-pox. Proc Soc Exp Biol Med 30:892–894. doi:10.3181/00379727-30-6724.
    1. Li G, Chen N, Roper RL, Feng Z, Hunter A, Danila M, Lefkowitz EJ, Buller RM, Upton C. 2005. Complete coding sequences of the rabbitpox virus genome. J Gen Virol 86:2969–2977. doi:10.1099/vir.0.81331-0.
    1. Adams MM, Rice AD, Moyer RW. 2007. Rabbitpox virus and vaccinia virus infection of rabbits as a model for human smallpox. J Virol 81:11084–11095. doi:10.1128/JVI.00423-07.
    1. Nalca A, Nichols DK. 2011. Rabbitpox: a model of airborne transmission of smallpox. J Gen Virol 92:31–35. doi:10.1099/vir.0.026237-0.
    1. Roy CJ, Voss TG. 2010. Use of the aerosol rabbitpox virus model for evaluation of anti-poxvirus agents. Viruses 2:2096–2107. doi:10.3390/v2092096.
    1. Perry MR, Warren R, Merchlinsky M, Houchens C, Rogers JV. 2018. Rabbitpox in New Zealand white rabbits: a therapeutic model for evaluation of poxvirus medical countermeasures under the FDA Animal Rule. Front Cell Infect Microbiol 8:356. doi:10.3389/fcimb.2018.00356.
    1. Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, Barone L, Burns C, Rhodes G, Tohan S, Huggins JW, Baker RO, Buller RL, Touchette E, Waller K, Schriewer J, Neyts J, DeClercq E, Jones K, Hruby D, Jordan R. 2005. An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J Virol 79:13139–13149. doi:10.1128/JVI.79.20.13139-13149.2005.
    1. Duraffour S, Snoeck R, de Vos R, van Den Oord JJ, Crance JM, Garin D, Hruby DE, Jordan R, De Clercq E, Andrei G. 2007. Activity of the anti-orthopoxvirus compound ST-246 against vaccinia, cowpox and camelpox viruses in cell monolayers and organotypic raft cultures. Antivir Ther 12:1205–1216.
    1. Smith SK, Olson VA, Karem KL, Jordan R, Hruby DE, Damon IK. 2009. In vitro efficacy of ST246 against smallpox and monkeypox. Antimicrob Agents Chemother 53:1007–1012. doi:10.1128/AAC.01044-08.
    1. Jordan R, Leeds JM, Tyavanagimatt S, Hruby DE. 2010. Development of ST-246 for treatment of poxvirus infections. Viruses 2:2409–2435. doi:10.3390/v2112409.
    1. Duraffour S, Lorenzo MM, Zoller G, Topalis D, Grosenbach D, Hruby DE, Andrei G, Blasco R, Meyer H, Snoeck R. 2015. ST-246 is a key antiviral to inhibit the viral F13L phospholipase, one of the essential proteins for orthopoxvirus wrapping. J Antimicrob Chemother 70:1367–1380. doi:10.1093/jac/dku545.
    1. Vora S, Damon I, Fulginiti V, Weber SG, Kahana M, Stein SL, Gerber SI, Garcia-Houchins S, Lederman E, Hruby D, Collins L, Scott D, Thompson K, Barson JV, Regnery R, Hughes C, Daum RS, Li Y, Zhao H, Smith S, Braden Z, Karem K, Olson V, Davidson W, Trindade G, Bolken T, Jordan R, Tien D, Marcinak J. 2008. Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin Infect Dis 46:1555–1561. doi:10.1086/587668.
    1. Centers for Diseases Control and Prevention. 2009. Progressive vaccinia in a military smallpox vaccinee—United States, 2009. MMWR Mob Mortal Wkly Rep 58:532–536.
    1. Lederman ER, Davidson W, Groff HL, Smith SK, Warkentien T, Li Y, Wilkins KA, Karem KL, Akondy RS, Ahmed R, Frace M, Shieh WJ, Zaki S, Hruby DE, Painter WP, Bergman KL, Cohen JI, Damon IK. 2012. Progressive vaccinia: case description and laboratory-guided therapy with vaccinia immune globulin, ST-246, and CMX001. J Infect Dis 206:1372–1385. doi:10.1093/infdis/jis510.
    1. Mucker EM, Goff AJ, Shamblin JD, Grosenbach DW, Damon IK, Mehal JM, Holman RC, Carroll D, Gallardo N, Olson VA, Clemmons CJ, Hudson P, Hruby DE. 2013. Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (smallpox). Antimicrob Agents Chemother 57:6246–6253. doi:10.1128/AAC.00977-13.
    1. Berhanu A, Prigge JT, Silvera PM, Honeychurch KM, Hruby DE, Grosenbach DW. 2015. Treatment with the smallpox antiviral tecovirimat (ST-246) alone or in combination with ACAM2000 vaccination is effective as a postsymptomatic therapy for monkeypox virus infection. Antimicrob Agents Chemother 59:4296–4300. doi:10.1128/AAC.00208-15.
    1. Nalca A, Hatkin JM, Garza NL, Nichols DK, Norris SW, Hruby DE, Jordan R. 2008. Evaluation of orally delivered ST-246 as postexposure prophylactic and antiviral therapeutic in an aerosolized rabbitpox rabbit model. Antiviral Res 79:121–127. doi:10.1016/j.antiviral.2008.03.005.
    1. Jordan R, Tien D, Bolken TC, Jones KF, Tyavanagimatt SR, Strasser J, Frimm A, Corrado ML, Strome PG, Hruby DE. 2008. Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor. Antimicrob Agents Chemother 52:1721–1727. doi:10.1128/AAC.01303-07.
    1. Chinsangaram J, Honeychurch KM, Tyavanagimatt SR, Leeds JM, Bolken TC, Jones KF, Jordan R, Marbury T, Ruckle J, Mee-Lee D, Ross E, Lichtenstein I, Pickens M, Corrado M, Clarke JM, Frimm AM, Hruby DE. 2012. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers. Antimicrob Agents Chemother 56:4900–4905. doi:10.1128/AAC.00904-12.
    1. Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, Lovejoy C, Meara I, Long P, Hruby DE. 2018. Oral tecovirimat for the treatment of smallpox. N Engl J Med 379:44–53. doi:10.1056/NEJMoa1705688.
    1. Russo AT, Grosenbach DW, Brasel TL, Baker RO, Cawthon AG, Reynolds E, Bailey T, Kuehl PJ, Sugita V, Agans K, Hruby DE. 2018. Effects of treatment delay on efficacy of tecovirimat following lethal aerosol monkeypox virus challenge in cynomolgus macaques. J Infect Dis 218:1490–1499. doi:10.1093/infdis/jiy326.
    1. Hoy SM. 2018. Tecovirimat: first global approval. Drugs 78:1377–1382. doi:10.1007/s40265-018-0967-6.
    1. Merchlinsky M, Albright A, Olson V, Schiltz H, Merkeley T, Hughes C, Petersen B, Challberg M. 2019. The development and approval of tecoviromat (TPOXX), the first antiviral against smallpox. Antiviral Res 168:168–174. doi:10.1016/j.antiviral.2019.06.005.
    1. Beadle JR. 2007. Synthesis of cidofovir and (S)-HPMPA ether lipid prodrugs. Curr Protoc Nucleic Acids Chem Chapter 15:Unit 15.2. doi:10.1002/0471142700.nc1502s29.
    1. De Clercq E, Holy A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC. 1986. A novel selective broad-spectrum anti-DNA virus agent. Nature 323:464–467. doi:10.1038/323464a0.
    1. Davies EG, Thrasher A, Lacey K, Harper J. 1999. Topical cidofovir for severe molluscum contagiosum. Lancet 353:2042. doi:10.1016/s0140-6736(99)01782-1.
    1. Neyts J, De Clercq E. 1993. Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine for the treatment of lethal vaccinia virus infections in severe combined immune deficiency (SCID) mice. J Med Virol 41:242–246. doi:10.1002/jmv.1890410312.
    1. Smee DF, Bailey KW, Wong M, Sidwell RW. 2000. Intranasal treatment of cowpox virus respiratory infections in mice with cidofovir. Antiviral Res 47:171–177. doi:10.1016/s0166-3542(00)00105-4.
    1. Smee DF, Sidwell RW, Kefauver D, Bray M, Huggins JW. 2002. Characterization of wild-type and cidofovir-resistant strains of camelpox, cowpox, monkeypox, and vaccinia viruses. Antimicrob Agents Chemother 46:1329–1335. doi:10.1128/aac.46.5.1329-1335.2002.
    1. Smee DF. 2008. Progress in the discovery of compounds inhibiting orthopoxviruses in animal models. Antivir Chem Chemother 19:115–124. doi:10.1177/095632020801900302.
    1. Neyts J, Leyssen P, Verbeken E, De Clercq E. 2004. Efficacy of cidofovir in a murine model of disseminated progressive vaccinia. Antimicrob Agents Chemother 48:2267–2273. doi:10.1128/AAC.48.6.2267-2273.2004.
    1. Huggins JS, Martinez MJ, Bray M. 1998. Cidofovir (HPMPC) treatment of monkeypox. Antiviral Res 37:A73.
    1. Huggins JW, Zwiers SH, Baker RO, Hensley LE, Larsen T, Martinez MJ, Jahrling PB. 2003. Cidofovir treatment of variola (smallpox) in the hemorrhagic smallpox primate model and the IV monkeypox primate model. Antiviral Res 57:A78.
    1. Huggins JW, Martinez M, Hartmann CJ, Hensley LE, Jackson DL, Kefauver DF, Kulesh D, Larsen T, Miller DM, Mucker E, Shamblin JD, Tate M, Whitehouse CA, Zwiers SH, Jahrling P. 2004. Successful cidofovir treatment of smallpox-like disease in Variola and monkeypox primate models. Antiviral Res 62:A57–A58.
    1. Verreault D, Sivasubramani SK, Talton JD, Doyle LA, Reddy JD, Killeen SZ, Didier PJ, Marx PA, Roy CJ. 2012. Evaluation of inhaled cidofovir as postexposure prophylactic in an aerosol rabbitpox model. Antiviral Res 93:204–208. doi:10.1016/j.antiviral.2011.11.013.
    1. Hostetler KY. 2010. Synthesis and early development of hexadecyloxypropylcidofovir: an oral antipoxvirus nucleoside phosphonate. Viruses 2:2213–2225. doi:10.3390/v2102213.
    1. Magee WC, Hostetler KY, Evans DH. 2005. Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate. Antimicrob Agents Chemother 49:3153–3162. doi:10.1128/AAC.49.8.3153-3162.2005.
    1. Jesus DM, Costa LT, Goncalves DL, Achete CA, Attias M, Moussatche N, Damaso CR. 2009. Cidofovir inhibits genome encapsidation and affects morphogenesis during the replication of vaccinia virus. J Virol 83:11477–11490. doi:10.1128/JVI.01061-09.
    1. Tarbouriech N, Ducournau C, Hutin S, Mas PJ, Man P, Forest E, Hart DJ, Peyrefitte CN, Burmeister WP, Iseni F. 2017. The vaccinia virus DNA polymerase structure provides insights into the mode of processivity factor binding. Nat Commun 8:1455. doi:10.1038/s41467-017-01542-z.
    1. Olson VA, Smith SK, Foster S, Li Y, Lanier ER, Gates I, Trost LC, Damon IK. 2014. In vitro efficacy of brincidofovir against variola virus. Antimicrob Agents Chemother 58:5570–5571. doi:10.1128/AAC.02814-14.
    1. Kern ER, Hartline C, Harden E, Keith K, Rodriguez N, Beadle JR, Hostetler KY. 2002. Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob Agents Chemother 46:991–995. doi:10.1128/aac.46.4.991-995.2002.
    1. Parker S, Touchette E, Oberle C, Almond M, Robertson A, Trost LC, Lampert B, Painter G, Buller RM. 2008. Efficacy of therapeutic intervention with an oral ether-lipid analogue of cidofovir (CMX001) in a lethal mousepox model. Antiviral Res 77:39–49. doi:10.1016/j.antiviral.2007.08.003.
    1. Rice AD, Adams MM, Lampert B, Foster S, Robertson A, Painter G, Moyer RW. 2011. Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses 3:63–82. doi:10.3390/v3020063.
    1. Rice AD, Adams MM, Wallace G, Burrage AM, Lindsey SF, Smith AJ, Swetnam D, Manning BR, Gray SA, Lampert B, Foster S, Lanier R, Robertson A, Painter G, Moyer RW. 2011. Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses 3:47–62. doi:10.3390/v3010047.
    1. Grossi IM, Foster SA, Gainey MR, Krile RT, Dunn JA, Brundage T, Khouri JM. 2017. Efficacy of delayed brincidofovir treatment against a lethal rabbitpox virus challenge in New Zealand White rabbits. Antiviral Res 143:278–286. doi:10.1016/j.antiviral.2017.04.002.
    1. Ciesla SL, Trahan J, Wan WB, Beadle JR, Aldern KA, Painter GR, Hostetler KY. 2003. Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral Res 59:163–171. doi:10.1016/s0166-3542(03)00110-4.
    1. Chittick G, Morrison M, Brundage T, Nichols WG. 2017. Short-term clinical safety profile of brincidofovir: a favorable benefit-risk proposition in the treatment of smallpox. Antiviral Res 143:269–277. doi:10.1016/j.antiviral.2017.01.009.
    1. Sauerbrei A, Meier C, Meerbach A, Schiel M, Helbig B, Wutzler P. 2005. In vitro activity of cycloSal-nucleoside monophosphates and polyhydroxycarboxylates against orthopoxviruses. Antiviral Res 67:147–154. doi:10.1016/j.antiviral.2005.06.001.
    1. Fan X, Zhang X, Zhou L, Keith KA, Kern ER, Torrence PF. 2006. 5-(Dimethoxymethyl)-2′-deoxyuridine: a novel gem diether nucleoside with anti-orthopoxvirus activity. J Med Chem 49:3377–3382. doi:10.1021/jm0601710.
    1. Fan X, Zhang X, Zhou L, Keith KA, Prichard MN, Kern ER, Torrence PF. 2006. Toward orthopoxvirus countermeasures: a novel heteromorphic nucleoside of unusual structure. J Med Chem 49:4052–4054. doi:10.1021/jm060404n.
    1. Fan X, Zhang X, Zhou L, Keith KA, Kern ER, Torrence PF. 2006. A pyrimidine-pyrazolone nucleoside chimera with potent in vitro anti-orthopoxvirus activity. Bioorg Med Chem Lett 16:3224–3228. doi:10.1016/j.bmcl.2006.03.043.
    1. Chu CK, Jin YH, Baker RO, Huggins J. 2003. Antiviral activity of cyclopentenyl nucleosides against orthopox viruses (smallpox, monkeypox and cowpox). Bioorg Med Chem Lett 13:9–12. doi:10.1016/s0960-894x(02)00841-7.
    1. Smee DF, Hurst BL, Wong MH, Glazer RI, Rahman A, Sidwell RW. 2007. Efficacy of N-methanocarbathymidine in treating mice infected intranasally with the IHD and WR strains of vaccinia virus. Antiviral Res 76:124–129. doi:10.1016/j.antiviral.2007.06.005.
    1. Prichard MN, Keith KA, Quenelle DC, Kern ER. 2006. Activity and mechanism of action of N-methanocarbathymidine against herpesvirus and orthopoxvirus infections. Antimicrob Agents Chemother 50:1336–1341. doi:10.1128/AAC.50.4.1336-1341.2006.
    1. Kern ER, Prichard MN, Quenelle DC, Keith KA, Tiwari KN, Maddry JA, Secrist JA III. 2009. Activities of certain 5-substituted 4′-thiopyrimidine nucleosides against orthopoxvirus infections. Antimicrob Agents Chemother 53:572–579. doi:10.1128/AAC.01257-08.
    1. Prichard MN, Kern ER. 2010. Antiviral activity of 4′-thioIDU and thymidine analogs against orthopoxviruses. Viruses 2:1968–1983. doi:10.3390/v2091968.
    1. Duraffour S, Drillien R, Haraguchi K, Balzarini J, Topalis D, van den Oord JJ, Andrei G, Snoeck R. 2014. KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo. Antimicrob Agents Chemother 58:27–37. doi:10.1128/AAC.01601-13.
    1. Mazurkov OY, Kabanov AS, Shishkina LN, Sergeev AA, Skarnovich MO, Bormotov NI, Skarnovich MA, Ovchinnikova AS, Titova KA, Galahova DO, Bulychev LE, Sergeev AA, Taranov OS, Selivanov BA, Tikhonov AY, Zavjalov EL, Agafonov AP, Sergeev AN. 2016. New effective chemically synthesized anti-smallpox compound NIOCH-14. J Gen Virol 97:1229–1239. doi:10.1099/jgv.0.000422.
    1. WHO. 2016. WHO Advisory Committee on Variola Virus Research: report of the seventeenth meeting. World Health Organization, Geneva, Switzerland: .
    1. WHO. 2016. WHO Advisory Committee on Variola Virus Research: report of the eighteenth meeting. World Health Organization, Geneva, Switzerland: .
    1. Smee DF, Wong MH, Hurst BL, Ennis J, Turner JD. 2013. Effects of nasal or pulmonary delivered treatments with an adenovirus vectored interferon (mDEF201) on respiratory and systemic infections in mice caused by cowpox and vaccinia viruses. PLoS One 8:e68685. doi:10.1371/journal.pone.0068685.
    1. Ladnyj ID, Ziegler P, Kima E. 1972. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ 46:593–597.
    1. McCollum AM, Damon IK. 2014. Human monkeypox. Clin Infect Dis 58:260–267. doi:10.1093/cid/cit703.
    1. Likos AM, Sammons SA, Olson VA, Frace AM, Li Y, Olsen-Rasmussen M, Davidson W, Galloway R, Khristova ML, Reynolds MG, Zhao H, Carroll DS, Curns A, Formenty P, Esposito JJ, Regnery RL, Damon IK. 2005. A tale of two clades: monkeypox viruses. J Gen Virol 86:2661–2672. doi:10.1099/vir.0.81215-0.
    1. Reed KD, Melski JW, Graham MB, Regnery RL, Sotir MJ, Wegner MV, Kazmierczak JJ, Stratman EJ, Li Y, Fairley JA, Swain GR, Olson VA, Sargent EK, Kehl SC, Frace MA, Kline R, Foldy SL, Davis JP, Damon IK. 2004. The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med 350:342–350. doi:10.1056/NEJMoa032299.
    1. Trindade GS, Emerson GL, Carroll DS, Kroon EG, Damon IK. 2007. Brazilian vaccinia viruses and their origins. Emerg Infect Dis 13:965–972. doi:10.3201/eid1307.061404.
    1. Abrahão JS, Campos RK, Trindade GDS, Guimarães da Fonseca F, Ferreira PCP, Kroon EG. 2015. Outbreak of severe zoonotic vaccinia virus infection, Southeastern Brazil. Emerg Infect Dis 21:695–698. doi:10.3201/eid2104.140351.
    1. Bera BC, Shanmugasundaram K, Barua S, Venkatesan G, Virmani N, Riyesh T, Gulati BR, Bhanuprakash V, Vaid RK, Kakker NK, Malik P, Bansal M, Gadvi S, Singh RV, Yadav V, Sardarilal, Nagarajan G, Balamurugan V, Hosamani M, Pathak KM, Singh RK. 2011. Zoonotic cases of camelpox infection in India. Vet Microbiol 152:29–38. doi:10.1016/j.vetmic.2011.04.010.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner