Searching for Anti-Cancer and Anti-Parasite Leads from Filamentous Fungi

71 Pages·2014·3.39 MB·English

by  Marcelo Meletti

Searching for Anti-Cancer and Anti-Parasite
Leads from Filamentous Fungi
Cedric Pearce, Ph.D
Mycosynthetix, Inc.
Sao Paulo, Brasil 2014
Outline
•
basic mycology
•
history of fungus metabolites
•
out approach to isolation and
characterization
•
National Cancer Institute funded project
•
antiparasitic research malaria/leishmaniasis
•
crop protection work on bioherbicides
Basic Mycology - Fungi
• Eukaryotes
– genetically closer to animals than plants
• Heterotrophic aerobes
– require organic carbon source
• Adapted to many
substrates/environments
– ubiquitous
• 1.5-5 million species
– 75,000 described in literature
• Talented synthetic chemists
– 12,000 unique compounds cataloged
• THE MAJORITY OF FUNGI HAVE NEVER
BEEN EVALAUTED
Fungal Metabolism and Secondary Metabolites
substrate
nutrients extra cellular enzymes
primary metabolism
fungal cell
organic acids, simple sugars, amino acids
secondary metabolism cell components
e.g. brefeldin A – P.decumbens e.g. gliotoxin - Aspergillus fumigatus
e.g. lentinan - Lentinus edodes

1,200 years of fungal based medicines
ten important products
From top left to bottom right .... Red yeast rice (800AD), psilocybin
(middle ages), penicillin, cephalosporin, LSD,
1,200 years of fungal based medicines
ten important products
part II
From top left to bottom right .... lentinan - Lentinus edodes,
cyclosporin, statins, strobilurins, cancidas and finally, Gilenya
(approved for MS October 2010)
Cherilyn R. Strader, Cedric J. Pearce, and Nicholas H. Oberlies. Fingolimod (FTY720): A Recently
Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite. Journal of Natural 6
Products, 2011, 74, 900-907. PMID:21456524; doi: 10.1021/np2000528
240,000 Compounds from Nature
High-throughput Profiling of Microbial Extracts
Tatsuya Ito, Takamichi Odake, Hideyuki Katoh, Yuichi Yamaguchi, Masahiro Aoki
J Nat Prod 2011 74 983-988
•Analysis of 13,000 fungi showed an average of between 1.04 and 1.73 unique
compounds per sample.
Theoretically...
• number of fungi - 1.5 million - Hawkesworth
• other ranges up to 5.1 million (Blackwell Am. J. Bot. March 2011 vol. 98 426-438)

• number of secondary metabolites
• ~ 2 unique compounds per strain studied
• up to 30 silent pathways - e.g. polyketides

• ~12,000 fungal metabolites in the literature

• where are the remaining 3-10 million metabolites?