Natural Product-Based Drug Discovery in Africa: The Need for Integration into Modern Drug Discovery Paradigms

Chapter

Abstract

A myriad of infectious diseases continue to cause the death and suffering of millions of people in sub-Saharan Africa. Efforts to mitigate this suffering involve, among others, concerted efforts at discovering and developing new and more efficacious therapies for these diseases. To support these efforts, the full potential of Africa’s rich and vibrant biodiversity as a source of lead compounds and drug candidates needs to be harnessed. This would require a complete reevaluation of how natural product drug discovery is conducted on the continent, and in this chapter, we describe some of the components that could underpin this proposed transformation.

Keywords

Natural Product Drug Discovery Antiplasmodial Activity Natural Product Research Drug Discovery Effort 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ABPP

Activity-based protein profiling

ACE

Angiotensin-converting enzyme

ADME

Absorption, distribution, metabolism, and excretion

ALNAP

African Laboratory for Natural Products

CIS

Chemical Information System

CYP

Cytochrome

DNDi

Drugs for Neglected Diseases Initiative

HAART

Highly active antiretroviral therapy

HTS

High-throughput screening

MMV

Medicines for Malaria Venture

NABSA

Network for Analytical and Bioassay Services in Africa

NAPRECA

Natural Products Research Network for East and Central Africa

RITAM

Research Initiative on Traditional Antimalarial Methods

SANBI

South African National Biodiversity Institute

SAR

Structure-activity relationship

TB

Tuberculosis

UCT

University of Cape Town

VAO

Vanillyl-alcohol oxidase

WRAIR

Walter Reed Army Institute of Research

wwPDB

Worldwide Protein Data Bank

References

  1. 1.
    World Health Organization. Traditional Medicine Strategy. 2002–2005.Google Scholar
  2. 2.
    Willcox ML, Bodeker G (2004) Traditional herbal medicines for malaria. Br Med J 329:1156–1159CrossRefGoogle Scholar
  3. 3.
    Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477CrossRefGoogle Scholar
  4. 4.
    Itokawa H, Morris-Natschke SL, Akiyama T et al (2008) Plant-derived natural product research aimed at new drug discovery. J Nat Med 62:263–280CrossRefGoogle Scholar
  5. 5.
    Wang M-W, Hao X, Chen K (2007) Biological screening of natural products and drug innovation in China. Phil Trans R Soc Lond B Biol Sci 362:1093–1105CrossRefGoogle Scholar
  6. 6.
    Saxena S, Pant N, Jain DC et al (2003) Antimalarial agents from plant sources. Curr Sci 85:1314–1329Google Scholar
  7. 7.
    Clardy J, Fischbach MA, Walsh CT (2006) New antibiotics from bacterial natural products. Nat Biotechnol 24:1541–1550CrossRefGoogle Scholar
  8. 8.
    Butler MS (2005) Natural products to drugs: natural product derived compounds in clinical trials. Nat Prod Rep 22:162–195CrossRefGoogle Scholar
  9. 9.
    Gutierrez-Lugo M-T, Bewley CA (2008) Natural Products, Small Molecules, and Genetics in Tuberculosis Drug Development. J Med Chem 51:2606–2612CrossRefGoogle Scholar
  10. 10.
    Fleming A (1922) On a remarkable bacteriolytic element found in tissues and secretions. Phil Trans R Soc Lond B Biol Sci 93:306–317CrossRefGoogle Scholar
  11. 11.
    Hare R (1982) New light on the history of Penicillin. Med Hist 26:1–24CrossRefGoogle Scholar
  12. 12.
    Wells TNC (2011) Natural products as starting points for future antimalarial therapies: going back to our roots? Malar J 10(Suppl 1):S3CrossRefGoogle Scholar
  13. 13.
    Klayman DL (1985) Quinghaosu (artemisinin): an antimalarial drug from China. Science 228:1049–1055CrossRefGoogle Scholar
  14. 14.
    Haynes RK (2006) From artemisinin to new artemisinin antimalarials: biosynthesis, extraction, old and new derivatives, stereochemistry and medicinal chemistry requirements. Curr Top Med Chem 6:509–537CrossRefGoogle Scholar
  15. 15.
    Charman SA, Arbe-Barnes S, Bathurst I et al (2011) Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci USA 108:4400–4405CrossRefGoogle Scholar
  16. 16.
    Vennerstrom JL, Arbe-Barnes S, Brun R et al (2002) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430:900–904CrossRefGoogle Scholar
  17. 17.
    van Wyk AWW, Lobb KA, Caira MR et al (2007) Transformations of manool. Tri- and tetracyclic norditerpenoids with in vitro activity against plasmodium falciparum. J Nat Prod 70:1253–1258CrossRefGoogle Scholar
  18. 18.
    Pillay P, Vleggaar R, Maharaj VJ et al (2007) Antiplasmodial hirsutinolides from Vernonia staehelinoides and their utilization towards a simplified pharmacophore. Phytochemistry 68:1200–1205CrossRefGoogle Scholar
  19. 19.
    Li JW-H, Vederas JC (2009) Drug discovery and natural products: end of an era or an endless frontier? Science 325:161–165CrossRefGoogle Scholar
  20. 20.
    Trouiller P, Olliaro P, Torreele E et al (2002) Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 359:2188–2194CrossRefGoogle Scholar
  21. 21.
    Nyigo VA, Malebo HM (2005) Drug discovery and developments in developing countries: bottlenecks and way forward. Tanzan Health Res Bull 7:154–158Google Scholar
  22. 22.
    Chibale K (2010) Discovering Africa’s drug potential. http://www.scidev.net/en/opinions/discovering-africa-s-drug-potential.html. Accessed June 2011
  23. 23.
    Bero J, Frederich M, Quetin-Leclercq J (2009) Antimalarial compounds isolated from plants used in traditional medicine. J Pharm Pharmacol 61:1401–1433CrossRefGoogle Scholar
  24. 24.
    Gamo F-J, Sanz LM, Vidal J et al (2010) Thousands of chemical starting points for antimalarial lead identification. Nature 465:305–310CrossRefGoogle Scholar
  25. 25.
    Guantai EM, Chibale K (2011) How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials? Malar J 10(Suppl 1):S2CrossRefGoogle Scholar
  26. 26.
    Guantai EM, Masimirembwa C, Chibale K (2011) Extracting molecular information from African natural products to facilitate unique African-led drug-discovery efforts. Future Med Chem 3:257–261CrossRefGoogle Scholar
  27. 27.
    The University of Arizona’s Natural Products Database. http://npd.chem.arizona.edu/. Accessed June 2011.
  28. 28.
    Queensland Compound Library. http://www.griffith.edu.au/science/queensland-compound-library. Accessed June 2011.
  29. 29.
    Bajorath J (2002) Chemoinformatics methods for systematic comparison of molecules from natural and synthetic sources and design of hybrid libraries. J Comput Aided Mol Des 16:431–439CrossRefGoogle Scholar
  30. 30.
    Coon MJ (2005) Cytochrome P450: nature’s most versatile biological catalyst. Annu Rev Pharmacol Toxicol 45:1–25CrossRefGoogle Scholar
  31. 31.
    Fura A, Shu Y-Z, Zhu M et al (2004) Discovering drugs through biological transformation: role of pharmacologically active metabolites in drug discovery. J Med Chem 47:4339–4350CrossRefGoogle Scholar
  32. 32.
    Gonzalez FJ, Nebert DW (1990) Evolution of the P450 gene superfamily: animal-plant ‘warfare’, molecular drive and human genetic differences in drug oxidation. Trends Genet 6:182–186CrossRefGoogle Scholar
  33. 33.
    Projean O, Baune B, Farinotti R et al (2003) In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4 and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Dispos 31:748–754CrossRefGoogle Scholar
  34. 34.
    Fu S, Björkman A, Wåhlin B et al (1986) In vitro activity of chloroquine, the two enantiomers of chloroquine, desethylchloroquine and pyronaridine against Plasmodium falciparum. Br J Clin Pharmacol 22:93–96Google Scholar
  35. 35.
    Mesia K, Cimanga RK, Dhooge L et al (2010) Antimalarial activity and toxicity evaluation of a quantified Nauclea pobeguinii extract. J Ethnopharmacol 131:10–16CrossRefGoogle Scholar
  36. 36.
    Smit MS (2011) Comparison of recombinant E. coli- and yeast-based whole cell hydroxylating biocatalysts (Abstract). http://lamp3.tugraz.at/~acib/index.php/wbNews/detail/44. Accessed June 2011
  37. 37.
    University of Cape Town Centre for Bioprocess Engineering Research. http://www.chemeng.uct.ac.za/research/bioprocess/. Accessed June 2011
  38. 38.
    Claus BL, Underwood DJ (2002) Discovery informatics: its evolving role in drug discovery. Drug Discov Today 7:957–966CrossRefGoogle Scholar
  39. 39.
    Terstappen GC, Reggiani A (2001) In silico research in drug discovery. Trends Pharmacol Sci 22:23–26CrossRefGoogle Scholar
  40. 40.
    Bajorath J (2001) Rational drug discovery revisited: interfacing experimental programs with bio- and chemo-informatics. Drug Discov Today 6:989–995CrossRefGoogle Scholar
  41. 41.
    Moitessier N, Englebienne P, Lee D et al (2008) Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go. Br J Pharmacol 153:S7–S26CrossRefGoogle Scholar
  42. 42.
    Sanger Institute GeneDB Project. http://www.genedb.org/Homepage. Accessed June 2011
  43. 43.
    The TDR Targets Database v5 - A chemogenomics resource for neglected tropical diseases. http://tdrtargets.org/. Accessed September 2011
  44. 44.
    Agüero F, Al-Lazikani B, Aslett M et al (2008) Genomic-scale prioritization of drug targets: the TDR Targets database. Nat Rev Drug Discov 7:900–907CrossRefGoogle Scholar
  45. 45.
    Worldwide Protein Data Bank (wwPDB). http://www.wwpdb.org/. Accessed June 2011
  46. 46.
    Jiang S, Zeng Q, Gettayacamin M et al (2005) Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs. Antimicrob Agents Chemother 49:1169–1176CrossRefGoogle Scholar
  47. 47.
    Yeung BKS, Zou B, Rottmann M (2010) Spirotetrahydro b-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 53:5155–5164CrossRefGoogle Scholar
  48. 48.
    Rottmann M, McNamara C, Yeung BKS (2010) Spiroindolones, a potent compound class for the treatment of malaria. Science 329:1175–1180CrossRefGoogle Scholar
  49. 49.
    Nchinda AT, Chibale K, Redelinghuys P et al (2006) Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme. Bioorg Med Chem Lett 16:4616–4619CrossRefGoogle Scholar
  50. 50.
    Butina D, Segall MD, Frankcombe K (2002) Predicting ADME properties in silico: methods and models. Drug Discov Today 7:S83–S88CrossRefGoogle Scholar
  51. 51.
    Yu H, Adedoyin A (2003) ADME–Tox in drug discovery: integration of experimental and computational technologies. Drug Discov Today 8:852–861CrossRefGoogle Scholar
  52. 52.
    Kerns EK, Di L (2008) Drug-like properties: concepts, structure, design and methods: from ADME to toxicity optimization. Academic Press/Elselvier, AmsterdamGoogle Scholar
  53. 53.
    Masimirembwa CM, Bredberg U, Andersson TB (2003) Metabolic stability for drug discovery and development: pharmacokinetic and biochemical challenges. Clin Pharmacokinet 42:515–528CrossRefGoogle Scholar
  54. 54.
    Eddershaw PJ, Beresford AP, Bayliss MK (2000) ADME/PK as part of a rational approach to drug discovery. Drug Discov Today 5:409–414CrossRefGoogle Scholar
  55. 55.
    Guantai EM, Ncokazi K, Egan TJ et al (2011) Enone- and chalcone-chloroquinoline hybrid analogues: in silico guided design, synthesis, antiplasmodial activity, in vitro metabolism, and mechanistic studies. J Med Chem 54:3637–3649CrossRefGoogle Scholar
  56. 56.
    Cruciani G, Pastor M, Guba W (2000) VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. Eur J Pharm Sci 11:S29–S39CrossRefGoogle Scholar
  57. 57.
    Cruciani G, Carosati E, de Boeck B et al (2005) Understanding metabolism in human cytochromes from the perspective of the chemist. J Med Chem 48:6970–6979CrossRefGoogle Scholar
  58. 58.
    Congrieve M, Carr R, Murray C (2003) A “Rule of Three” for fragment-based lead discovery? Drug Discov Today 8:876–877CrossRefGoogle Scholar
  59. 59.
    Oprea TI, Davis AM, Teague SJ et al (2001) Is there a difference between leads and drugs? a historical perspective. J Chem Inf Comput Sci 41:1308–1315CrossRefGoogle Scholar
  60. 60.
    Lipinski CA, Lombardo F, Dominy BW et al (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26CrossRefGoogle Scholar
  61. 61.
    Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1:337–341CrossRefGoogle Scholar
  62. 62.
    Fotouhi N, Gillespie P, Goodnow R Jr (2008) Lead generation: reality check on commonly held views. Expert Opin Drug Discov 3:733–744CrossRefGoogle Scholar
  63. 63.
    Ganesan A (2008) The impact of natural products upon modern drug discovery. Curr Opin Chem Biol 12:306–317CrossRefGoogle Scholar
  64. 64.
    Ndakala A, Gessner RK, Gitari PW et al (2011) Antimalarial pyrido[1,2-a]benzimidazoles. J Med Chem 54:4581–4589CrossRefGoogle Scholar
  65. 65.
    Cabrera DG, Douelle F, Feng T-S et al (2011) Novel orally active antimalarial thiazoles. J Med Chem 54:7713–7719CrossRefGoogle Scholar
  66. 66.
    Walsh JJ, Bell A (2009) Hybrid drugs for malaria. Curr Pharm Des 15:2970–2985CrossRefGoogle Scholar
  67. 67.
    Tietze LF, Bell HP, Chandrasekhar S (2003) Natural product hybrids as new leads for drug discovery. Angew Chem Int Ed Engl 42:3996–4028CrossRefGoogle Scholar
  68. 68.
    Coslédan F, Fraisse L, Pellet A et al (2008) Selection of a trioxaquine as an antimalarial drug candidate. Proc Natl Acad Sci USA 105:17579–17584CrossRefGoogle Scholar
  69. 69.
    Liu C, Strolb JS, Schilling JK et al (2004) Design, synthesis, and bioactivities of steroid-linked taxol analogues as potential targeted drugs for prostate and breast cancer. J Nat Prod 67:152–159CrossRefGoogle Scholar
  70. 70.
    Kuznetsova L, Chen J, Sun L et al (2006) Synthesis and evaluation of novel fatty acid-second genaration taxoid conjugates as promising anticancer agents. Bioorg Med Chem Lett 16:974–977CrossRefGoogle Scholar
  71. 71.
    World Health Organization (2003) Treatment of tuberculosis: guidelines for national programs, 3rd edn. World Health Organization, Geneva, SwitzerlandGoogle Scholar
  72. 72.
    World Health Organization (2009) Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents. World Health Organization, Geneva, SwitzerlandGoogle Scholar
  73. 73.
    Edwards G, Biagini GA (2006) Resisting resistance: dealing with the irrepressible problem of malaria. Br J Clin Pharmacol 61:690–693CrossRefGoogle Scholar
  74. 74.
    Mutabingwa TK (2005) Artemisinin-based combination therapies (ACTs): best hope for malaria but inaccessible to the needy. Acta Trop 95:305–315CrossRefGoogle Scholar
  75. 75.
    White N (1999) Antimalarial drug resistance and combination chemotherapy. Phil Trans R Soc Lond B Biol Sc 354:739–749CrossRefGoogle Scholar
  76. 76.
    Heamiswarya S, Kruthiventi AK, Doble M (2008) Synergism between natural products and antibiotics against infectious diseases. Phytomedicine 15:639–652CrossRefGoogle Scholar
  77. 77.
    Lin R-D, Chin Y-P, Lee M-H (2005) Antimicrobial activity of antibiotics in combination with natural flavonoids against clinical extended-spectrum b -lactamase (ESBL)-producing klebsiella pneumoniae. Phytother Res 19:612–617CrossRefGoogle Scholar
  78. 78.
    Hu Z-Q, Zhao W-H, Hara Y et al (2001) Epigallocatechin gallate synergy with ampicillin/sulbactam against 28 clinical isolates of methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 48:361–364CrossRefGoogle Scholar
  79. 79.
    Zhao W-H, Hu Z-Q, Okubo S et al (2001) Mechanism of synergy between epigallocatechin gallate and b-lactams against methicillin-resistant staphylococcus aureus. Antimicrob Agents Chemother 45:1737–1742CrossRefGoogle Scholar
  80. 80.
    Lian L-Y, Al-Helal M, Roslaini AM et al (2009) Glycerol: an unexpected major metabolite of energy metabolism by the human malaria parasite. Malar J 8:38CrossRefGoogle Scholar
  81. 81.
    Teng R, Junankar PR, Bubb WA et al (2009) Metabolite profiling of the intraerythrocytic malaria parasite Plasmodium falciparum by 1H NMR spectroscopy. NMR Biomed 22:292–302CrossRefGoogle Scholar
  82. 82.
    Holmes E (2010) The evolution of metabolic profiling in parasitology. Parasitology 137:1437–1449CrossRefGoogle Scholar
  83. 83.
    Cheng K-W, Wong C-C, Wang M et al (2010) Identification and characterization of molecular targets of natural products by mass spectrometry. Mass Spectrom Rev 29:126–155Google Scholar
  84. 84.
    Pucheault M (2008) Natural products: chemical instruments to apprehend biological symphony. Org Biomol Chem 6:424–432CrossRefGoogle Scholar
  85. 85.
    Harrigan GG, Brackett DJ, Boros LG (2005) Medicinal chemistry, metabolic profiling and drug target discovery: a role for metabolic profiling in reverse pharmacology and chemical genetics. Mini Rev Med Chem 5:13–20CrossRefGoogle Scholar
  86. 86.
    Cravatt BF, Wright AT, Kozarich JW (2008) Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu Rev Biochem 77:383–414CrossRefGoogle Scholar
  87. 87.
    Harvey AL (2008) Natural products in drug discovery. Drug Discov Today 13:894–901CrossRefGoogle Scholar
  88. 88.
    Böttcher T, Pitscheider M, Sieber SA (2010) Natural products and their biological targets: proteomic and metabolomic labeling strategies. Angew Chem Int Ed Engl 49:2680–2698CrossRefGoogle Scholar
  89. 89.
    Takenaka T (2001) Classical vs reverse pharmacology in drug discovery. BJU Int 88:7–10CrossRefGoogle Scholar
  90. 90.
    Cassera MB, Merino EF, Peres VJ et al (2007) Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum. Mem Inst Oswaldo Cruz 102:377CrossRefGoogle Scholar
  91. 91.
    Gardner MJ, Hall N, Fung E et al (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498–511CrossRefGoogle Scholar
  92. 92.
    The Plasmodium Genome Database Collaborative (2001) PlasmoDB: an integrative database of the Plasmodium falciparum genome.Tools for accessing and analyzing finished and unfinished sequence data. Nucleic Acids Res 29:66–69CrossRefGoogle Scholar
  93. 93.
    Fleischmann RD, Alland D, Eisen JA et al (2002) Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol 184:5479–5490CrossRefGoogle Scholar
  94. 94.
    Watts JM, Dang KK, Gorelick RJ et al (2009) Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460:711–716CrossRefGoogle Scholar
  95. 95.
    Pink R, Hudson A, Mouriés M-A et al (2005) Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov 4:727–740CrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Division of Pharmacology, School of PharmacyUniversity of NairobiNairobiKenya
  2. 2.Department of Chemistry and Institute of Infectious Disease and Molecular MedicineUniversity of Cape TownRondeboschSouth Africa

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