Malaria Drug Accelerator (MalDA)

The Malaria Drug Accelerator (MalDA) is a collaboration of 15 scientific laboratories funded by the Bill and Melinda Gates foundation to advance the development of new antimalarial drugs.

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Who are we?

The MALDA Consortium is an innovative target-guided discovery platform linking phenotypic hits to function for malaria. MALDA offers a new research paradigm that compliments the existing ways malaria drugs are discovered: A virtual pharmaceutical company.

How do we work together?

The MALDA Consortium is a collaboration between fifteen international groups, funded by BMGF.

State-of-the-art
Plasmodium-adapted
technology platforms






In vitro selections
    State-of-Art Bioinformatics
    chemoinformatics / SAR / cryoEM
Conditional knockdown studies
     Essentiality assays
CRISPR-Cas9 reverse engineering
     Bar coded cell lines
     Overexpression lines
Metabolomics/Lipidomics/RNA-seq
     Macromolecule biosynthesis inhibitor assays
In vivo resistance evaluation

In vitro selections

  1. Clone by limiting dilution
  2. Select in triplicate
  3. Clone again
  4. Whole Genome Sequencing
  5. Compare genomes

External data
ChEMBL deposition data
Sequencing deposition data
Protocols

MalDA Publications

  1. Ottilie, S, Luth, MR, Hellemann, E, Goldgof, GM, Vigil, E, Kumar, P et al.. Adaptive laboratory evolution in S. cerevisiae highlights role of transcription factors in fungal xenobiotic resistance. Commun Biol. 2022;5 (1):128. doi: 10.1038/s42003-022-03076-7. PubMed PMID:35149760 PubMed Central PMC8837787.
  2. Xie, SC, Metcalfe, RD, Mizutani, H, Puhalovich, T, Hanssen, E, Morton, CJ et al.. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. Proc Natl Acad Sci U S A. 2021;118 (39):. doi: 10.1073/pnas.2107213118. PubMed PMID:34548400 PubMed Central PMC8488693.
  3. Forte, B, Ottilie, S, Plater, A, Campo, B, Dechering, KJ, Gamo, FJ et al.. Prioritization of Molecular Targets for Antimalarial Drug Discovery. ACS Infect Dis. 2021;7 (10):2764-2776. doi: 10.1021/acsinfecdis.1c00322. PubMed PMID:34523908 PubMed Central PMC8608365.
  4. Summers, RL, Pasaje, CFA, Pisco, JP, Striepen, J, Luth, MR, Kumpornsin, K et al.. Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention. Cell Chem Biol. 2022;29 (2):191-201.e8. doi: 10.1016/j.chembiol.2021.07.010. PubMed PMID:34348113 PubMed Central PMC8878317.
  5. Murithi, JM, Deni, I, Pasaje, CFA, Okombo, J, Bridgford, JL, Gnädig, NF et al.. The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance. Cell Chem Biol. 2022;29 (5):824-839.e6. doi: 10.1016/j.chembiol.2021.06.006. PubMed PMID:34233174 PubMed Central PMC8727639.
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MalDA selections

  • 200+ compounds under investigation
  • 400+ resistant clones generated for 58 compounds, and whole genome sequenced
  • 1300+ single nucleotide variants, 700+ indels, and 160+ copy number variants observed
  • At least 23 potential drug targets and 14 potential resistance genes identified or re-discovered using this method

Targets

  • PFK9
  • RFC4
  • ARK1
  • ATP4
  • KRS
  • cyto-IRS
  • FTB
  • PIP5K
  • ACS11
  • APP
  • DHFR-TS
  • PI4K
  • ATPase2
  • FP2A
  • NCR1
  • cPheRS
  • DHODH
  • RRB1
  • DPAP1
  • PRS

Resistance Genes

  • MFR3
  • ABCI3
  • CARL
  • MDR1
  • AAT1
  • CRT
  • PARE
  • YHM2
  • NEK1
  • MRP2
  • TKL3
  • CAF16
  • SulP
  • PF3D7_0909700

Compounds under consideration

  • 2,7-dibromo
    Cryptolepine hydrochloride (analog)
  • ACT-451840
  • Altiratinib
  • Anacetrapib
  • artemether
  • Atovaquone
  • AZ412
  • BI-1230
  • BI-1388
  • BI-2536
  • BRD1095
  • BRD3444
  • Brefeldin A
  • CEP-37440
  • cladosporin
  • Clofazimine
  • Cryptolepine hydrochloride
  • DDD01025389
  • DDD01057375
  • DDD01061024
  • DDD01250400
  • DDD01254473
  • DDD01298810
  • Decoquinate
  • Desoxyepothilone B
  • DSM265
  • ELQ300
  • GNF-Pf-1618
  • GNF-Pf-2740
  • GNF-Pf-2775
  • GNF-Pf-3582
  • GNF-Pf-3600
  • GNF-Pf-3703
  • GNF-Pf-4216
  • GNF-Pf-4283
  • GNF-Pf-445
  • GNF-Pf-4492
  • GNF-Pf-4577
  • GNF-Pf-5129
  • GNF-pf-5310
  • GNF-Pf-5349
  • GNF-Pf-5458
  • GNF-Pf-5611
  • GNF-Pf-5648
  • GNF-pf-5660
  • GNF-Pf-5666
  • GNF-pf-5668
  • GNF-Pf-5675
  • GNF179
  • GNF452
  • GNF707
  • indolmycin
  • Ivermectin
  • KAE609
  • KAF156
  • KAI407
  • KDU691
  • Lomitapide
  • lopinavir
  • Mefloquine
  • milciclib maleate
  • MMV000248
  • MMV000442
  • MMV000478
  • MMV000570
  • MMV000787
  • MMV006169
  • MMV006172
  • MMV006357
  • MMV006455
  • MMV006767
  • MMV006833
  • MMV006901
  • MMV006962
  • MMV007181
  • MMV007224
  • MMV007564
  • MMV008149
  • MMV009063
  • MMV009108
  • MMV010545
  • MMV011438
  • MMV011772
  • MMV011895
  • MMV011903
  • MMV019017
  • MMV019066
  • MMV019189
  • MMV019313
  • MMV019555
  • MMV019662
  • MMV019719
  • MMV019721
  • MMV019881
  • MMV019993
  • MMV020623
  • MMV020746
  • MMV020750
  • MMV021735
  • MMV022224
  • MMV022478
  • MMV023367
  • MMV023388
  • MMV023949
  • MMV023985
  • MMV024038
  • MMV024114
  • MMV024406
  • MMV026596
  • MMV027496
  • MMV027634
  • MMV028038
  • MMV028895
  • MMV029272
  • MMV030084
  • MMV030666
  • MMV032967
  • MMV064286
  • MMV084864
  • MMV084978
  • MMV085071
  • MMV085203
  • MMV1007245
  • MMV1010248
  • MMV1029508
  • MMV1030932
  • MMV1042937
  • MMV1044457
  • MMV1068987
  • MMV1079594
  • MMV1088520
  • MMV1091186
  • MMV1094822
  • MMV1147256
  • MMV1214532
  • MMV1223789
  • MMV1271410
  • MMV1291222
  • MMV1312865
  • MMV1317269
  • MMV1319550
  • MMV1371622
  • MMV1385304
  • MMV1394623
  • MMV1421890
  • MMV1425891
  • MMV1427995
  • MMV1430193
  • MMV1431916
  • MMV1432165
  • MMV1432711
  • MMV1449124
  • MMV1451822
  • MMV1454442
  • MMV1458543
  • MMV1468363
  • MMV1490397
  • MMV1490405
  • MMV1490583
  • MMV1501496
  • MMV1528403
  • MMV1531441
  • MMV396736
  • MMV396797
  • MMV407834
  • MMV665785
  • MMV665789
  • MMV665794
  • MMV665824
  • MMV665852
  • MMV665882
  • MMV665888
  • MMV665924
  • MMV665928
  • MMV665939
  • MMV665941
  • MMV665943
  • MMV665971
  • MMV666080
  • MMV666687
  • MMV667491
  • MMV668311
  • MMV668399
  • MMV673482
  • MMV673964
  • MMV675939
  • MMV676380
  • MMV676881
  • Naphthoquine
  • Neu-1029
  • NEU-1931
  • NEU-4995
  • NITD678
  • OSM-S-106
  • Pentamidine isothionate
  • pepstatin butyl ester
  • Piperaquine
  • primaquine
  • Puromycin
  • Sapanisertib
  • SQ109
  • Suloctidil
  • TCMDC-124553
  • TCMDC-135051
  • TCMDC-135395
  • Tryptanthrin
  • Velpatasvir
  • Verapamil
  • ZSTK-474
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    Message us for inquiries regarding the MalDA project: ewinzeler@health.ucsd.edu

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