1932

Abstract

Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Together, these steps could result in accelerated timelines for bringing antiviral therapies to market so they can treat emerging infections and reduce human suffering.

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2017-01-06
2024-06-20
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Literature Cited

  1. Campbell GL, Marfin AA, Lanciotti RS, Gubler DJ. 1.  2002. West Nile virus. Lancet Infect. Dis. 2:519–29 [Google Scholar]
  2. Glass JD, Samuels O, Rich MM. 2.  2002. Poliomyelitis due to West Nile virus. N. Engl. J. Med. 347:1280–81 [Google Scholar]
  3. Lanciotti RS, Roehrig JT, Deubel V, Smith J, Parker M. 3.  et al. 1999. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286:2333–37 [Google Scholar]
  4. Leis AA, Stokic DS, Polk JL, Dostrow V, Winkelmann M. 4.  2002. A poliomyelitis-like syndrome from West Nile virus infection. N. Engl. J. Med. 347:1279–80 [Google Scholar]
  5. Gibney KB, Fischer M, Prince HE, Kramer LD, St. George K. 5.  et al. 2011. Chikungunya fever in the United States: a fifteen year review of cases. Clin. Infect. Dis. 52:e121–26 [Google Scholar]
  6. Khan K, Bogoch I, Brownstein JS, Miniota J, Nicolucci A. 6.  et al. 2014. Assessing the origin of and potential for international spread of chikungunya virus from the Caribbean. PLOS Curr. Outbreaks. doi: 10.1371/currents.outbreaks.2134a0a7bf37fd8d388181539fea2da5 [Google Scholar]
  7. Nhan TX, Claverie A, Roche C, Teissier A, Colleuil M. 7.  et al. 2014. Chikungunya virus imported into French Polynesia, 2014. Emerg. Infect. Dis. 20:1773–74 [Google Scholar]
  8. Drosten C, Meyer B, Muller MA, Corman VM, Al-Masri M. 8.  et al. 2014. Transmission of MERS-coronavirus in household contacts. N. Engl. J. Med. 371:828–35 [Google Scholar]
  9. Oboho IK, Tomczyk SM, Al-Asmari AM, Banjar AA, Al-Mugti H. 9.  et al. 2015. 2014 MERS-CoV outbreak in Jeddah—a link to health care facilities. N. Engl. J. Med. 372:846–54 [Google Scholar]
  10. Arden KE, Nissen MD, Sloots TP, Mackay IM. 10.  2005. New human coronavirus, HCoV-NL63, associated with severe lower respiratory tract disease in Australia. J. Med. Virol. 75:455–62 [Google Scholar]
  11. Bastien N, Anderson K, Hart L, Van Caeseele P, Brandt K. 11.  et al. 2005. Human coronavirus NL63 infection in Canada. J. Infect. Dis. 191:503–6 [Google Scholar]
  12. Kuiken T, Fouchier RAM, Schutten M, Rimmelzwaan GF, van Amerongen G. 12.  et al. 2003. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 362:263–70 [Google Scholar]
  13. van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P. 13.  et al. 2016. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N. Engl. J. Med. 374:33–42 [Google Scholar]
  14. Bah EI, Lamah MC, Fletcher T, Jacob ST, Brett-Major DM. 14.  et al. 2015. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N. Engl. J. Med. 372:40–47 [Google Scholar]
  15. Maganga GD, Kapetshi J, Berthet N, Kebela Ilunga B, Kabange F. 15.  et al. 2014. Ebola virus disease in the Democratic Republic of Congo. N. Engl. J. Med. 371:2083–91 [Google Scholar]
  16. Messacar K, Abzug MJ, Dominguez SR. 16.  2015. 2014 outbreak of enterovirus D68 in North America. J. Med. Virol. 88:739–45 [Google Scholar]
  17. Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL. 17.  et al. 2009. Zika virus outbreak on Yap Island, Federated States of Micronesia. N. Engl. J. Med. 360:2536–43 [Google Scholar]
  18. Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M. 18.  et al. 2016. Zika virus associated with microcephaly. N. Engl. J. Med. 374:951–58 [Google Scholar]
  19. Rubin EJ, Greene MF, Baden LR. 19.  2016. Zika virus and microcephaly. N. Engl. J. Med. 374:984–85 [Google Scholar]
  20. Fauci AS, Morens DM. 20.  2016. Zika virus in the Americas—yet another arbovirus threat. N. Engl. J. Med. 374:601–4 [Google Scholar]
  21. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T. 21.  et al. 2015. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N. Engl. J. Med. 373:1195–206 [Google Scholar]
  22. Asselah T, Boyer N, Saadoun D, Martinot-Peignoux M, Marcellin P. 22.  2016. Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives. Liver Int. 36:Suppl. 147–57 [Google Scholar]
  23. Li TC, Chan MC, Lee N. 23.  2015. Clinical implications of antiviral resistance in influenza. Viruses 7:4929–44 [Google Scholar]
  24. Lee SM, Yen HL. 24.  2012. Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection. Antivir. Res. 96:391–404 [Google Scholar]
  25. Lisziewicz J, Foli A, Wainberg M, Lori F. 25.  2003. Hydroxyurea in the treatment of HIV infection: clinical efficacy and safety concerns. Drug Saf. 26:605–24 [Google Scholar]
  26. Cox JT, Petry KU, Rylander E, Roy M. 26.  2004. Using imiquimod for genital warts in female patients. J. Women's Health 13:265–71 [Google Scholar]
  27. Naesens L, De Clercq E. 27.  2001. Recent developments in herpesvirus therapy. Herpes: J. IHMF 8:12–16 [Google Scholar]
  28. Cihlar T, Ray AS. 28.  2010. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiv. Res. 85:39–58 [Google Scholar]
  29. Jafri SM, Lok AS. 29.  2010. Antiviral therapy for chronic hepatitis B. Clin. Liver Dis. 14:425–38 [Google Scholar]
  30. Nakamura M, Kanda T, Haga Y, Sasaki R, Wu S. 30.  et al. 2016. Sofosbuvir treatment and hepatitis C virus infection. World J. Hepatol. 8:183–90 [Google Scholar]
  31. Feng JY, Xu Y, Barauskas O, Perry JK, Ahmadyar S. 31.  et al. 2015. Role of mitochondrial RNA polymerase in the toxicity of nucleotide inhibitors of hepatitis C virus. Antimicrob. Agents Chemother. 60:806–17 [Google Scholar]
  32. De Clercq E. 32.  2007. The acyclic nucleoside phosphonates from inception to clinical use: historical perspective. Antivir. Res. 75:1–13 [Google Scholar]
  33. Wensing AM, van Maarseveen NM, Nijhuis M. 33.  2010. Fifteen years of HIV protease inhibitors: raising the barrier to resistance. Antivir. Res. 85:59–74 [Google Scholar]
  34. De Luca A, Bianco C, Rossetti B. 34.  2014. Treatment of HCV infection with the novel NS3/4A protease inhibitors. Curr. Opin. Pharmacol. 18:9–17 [Google Scholar]
  35. Krishnan MN, Garcia-Blanco MA. 35.  2014. Targeting host factors to treat West Nile and dengue viral infections. Viruses 6:683–708 [Google Scholar]
  36. Noble CG, Chen YL, Dong H, Gu F, Lim SP. 36.  et al. 2010. Strategies for development of dengue virus inhibitors. Antivir. Res. 85:450–62 [Google Scholar]
  37. Behnam MAM, Nitsche C, Boldescu V, Klein CD. 37.  2016. The medicinal chemistry of dengue virus. J. Med. Chem. 59:5622–49 [Google Scholar]
  38. Cho A, Saunders OL, Butler T, Zhang L, Xu J. 38.  et al. 2012. Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg. Med. Chem. Lett. 22:2705–7 [Google Scholar]
  39. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL. 39.  et al. 2016. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531:381–85 [Google Scholar]
  40. Frye S, Crosby M, Edwards T, Juliano R. 40.  2011. US academic drug discovery. Nat. Rev. Drug Discov. 10:409–10 [Google Scholar]
  41. Slusher BS, Conn PJ, Frye S, Glicksman M, Arkin M. 41.  2013. Bringing together the academic drug discovery community. Nat. Rev. Drug Discov. 12:811–12 [Google Scholar]
  42. Everts M, Suto MJ, Painter GR, Whitley RJ. 42.  2016. Consortia's critical role in developing medical countermeasures for re-emerging viral infections: a USA perspective. Future Virol. 11:187–95 [Google Scholar]
  43. 43. DRIVE 2016. Drive Innovations. http://driveinnovations.org/
  44. Zhang JH, Chung TDY, Oldenburg KR. 44.  1999. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen. 4:67–73 [Google Scholar]
  45. Song Y, Chen W, Kang D, Zhang Q, Zhan P, Liu X. 45.  2014. “Old friends in new guise”: exploiting privileged structures for scaffold re-evolution/refining. Comb. Chem. High Throughput Screen. 17:536–53 [Google Scholar]
  46. Kowalski SP. 46.  2007. Freedom to operate: the preparations. Intellectual Property Management in Health and Agricultural Innovation: A Handbook of Best Practices A Krattiger, RT Mahoney, L Nelsen, JA Thomson, AB Bennett 1329–43 Oxford, UK: MIHR [Google Scholar]
  47. Scannell JW, Bosley J. 47.  2016. When quality beats quantity: decision theory, drug discovery, and the reproducibility crisis. PLOS ONE 11:e0147215 [Google Scholar]
  48. Bouvier NM, Lowen AC. 48.  2010. Animal models for influenza virus pathogenesis and transmission. Viruses 2:1530–63 [Google Scholar]
  49. Zompi S, Harris E. 49.  2012. Animal models of dengue virus infection. Viruses 4:62–82 [Google Scholar]
  50. Cook D, Brown D, Alexander R, March R, Morgan P. 50.  et al. 2014. Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nat. Rev. Drug Discov. 13:419–31 [Google Scholar]
  51. Baker M. 51.  2016. Biotech giant publishes failures to confirm high-profile science. Nature 530:141 [Google Scholar]
  52. Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW. 52.  et al. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLOS Med. 12:e1001815 [Google Scholar]
  53. Cox E, Borio L, Temple R. 53.  2014. Evaluating Ebola therapies—the case for RCTs. N. Engl. J. Med. 371:2350–51 [Google Scholar]
  54. Chow SC. 54.  2014. Adaptive clinical trial design. Annu. Rev. Med. 65:405–15 [Google Scholar]
  55. Jacobs M, Aarons E, Bhagani S, Buchanan R, Cropley I. 55.  et al. 2015. Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: a case-series of health-care workers. Lancet Infect. Dis. 15:1300–4 [Google Scholar]
  56. Naeger LK, Struble KA, Murray JS, Birnkrant DB. 56.  2010. Running a tightrope: regulatory challenges in the development of antiretrovirals. Antivir. Res. 85:232–40 [Google Scholar]
  57. 57. FDA (US Food Drug Admin.) 2015. FDA and accelerating the development of new pharmaceutical therapies White Pap., US Food Drug Admin., Silver Spring, MD. http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm439082.htm [Google Scholar]
  58. 58. FDA (US Food Drug Admin.) 2015. CDER breakthrough therapy designation approvals as of December 31, 2015 Rep., US Food Drug Admin., Silver Spring, MD. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/UCM481542.pdf [Google Scholar]
  59. Lyon GM, Mehta AK, Varkey JB, Brantly K, Plyler L. 59.  et al. 2014. Clinical care of two patients with Ebola virus disease in the United States. N. Engl. J. Med. 371:2402–9 [Google Scholar]
  60. Uyeki TM, Mehta AK, Davey RT Jr., Liddell AM, Wolf T. 60.  et al. 2016. Clinical management of Ebola virus disease in the United States and Europe. N. Engl. J. Med. 374:636–46 [Google Scholar]
  61. 61. US Dep. Health Hum. Serv., Food Drug Admin., Cent. Drug Eval. Res., Cent. Biol. Eval. Res 2015. Product development under the animal rule: guidance for industry. Rep., US Food Drug Admin., Silver Spring, MD. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm399217.pdf
  62. Norman T, Edwards A, Bountra C, Friend S. 62.  2011. The precompetitive space: time to move the yardsticks. Sci. Transl. Med. 3:76cm10 [Google Scholar]
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