Drug Information

Drug (ID: DG00232) and It's Reported Resistant Information

• Name: Piperaquine
• Synonyms: Piperaquinoline; Quinoline, 4,4'-(1,3-propanediyldi-4,1-piperazinediyl)bis(7-chloro-); Quinoline, 4,4'-(1,3-propanediyldi-4,1-piperazinediyl)bis(7-chloro-(9CI); 1,3-bis(1-(7-chloro-4'-quinolyl)-4'-piperazinyl)propane; 1,3-bis(4-(7'-chloro-4'-quinoline)-1-piperazine); 4,4'-(propane-1,3-diyldipiperazine-4,1-diyl)bis(7-chloroquinoline); 7-chloro-4-[4-[3-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propyl]piperazin-1-yl]quinoline
• Indication:
  In total 1 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1], [2], [3], [4]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [5]
• Target: Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A); NOUNIPROTAC; [1]
• Formula: C29H32Cl2N6
• IsoSMILES: C1CN(CCN1CCCN2CCN(CC2)C3=C4C=CC(=CC4=NC=C3)Cl)C5=C6C=CC(=CC6=NC=C5)Cl
• InChI: 1S/C29H32Cl2N6/c30-22-2-4-24-26(20-22)32-8-6-28(24)36-16-12-34(13-17-36)10-1-11-35-14-18-37(19-15-35)29-7-9-33-27-21-23(31)3-5-25(27)29/h2-9,20-21H,1,10-19H2
• InChIKey: UCRHFBCYFMIWHC-UHFFFAOYSA-N
• PubChem CID: 122262
• ChEBI ID: CHEBI:91231
• TTD Drug ID: D0P0SZ
• INTEDE ID: DR1296
• DrugBank ID: DB13941

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.H97Y
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: MIP probes and PCR sequencing assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.

Key Molecule: Chloroquine resistance transporter (CRT) [1], [4]

• Molecule Alteration: Missense mutation; p.F145I
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: MIP probes and PCR sequencing assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.

Key Molecule: Chloroquine resistance transporter (CRT) [1], [4]

• Molecule Alteration: Missense mutation; p.G353V
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: MIP probes and PCR sequencing assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.

Key Molecule: Chloroquine resistance transporter (CRT) [1], [4]

• Molecule Alteration: Missense mutation; p.M343L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: MIP probes and PCR sequencing assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: In contrast, gene-edited parasites with PfCRT H97Y, F145I, M343L, or G353V mutations are resistant to piperaquine in vitro.

Key Molecule: Chloroquine resistance transporter (CRT) [3]

• Molecule Alteration: Missense mutation; p.F145I + p.G353V+ p.I218F
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PacBio amplicon sequencing assay; Whole genome sequencing assay
• Experiment for Drug Resistance: Piperaquine susceptibility testing assay
• Mechanism Description: In parasites with single-copy pfpm2, those with the PfCRT F145I, G353V, or I218F mutations had a significantly greater log10-transformed piperaquine IC90 compared to Dd2 (linear regression; P <.0001, P =.0022, and P =.019, respectively), while other mutations did not show a significant difference in piperaquine IC90 compared to Dd2 (perhaps owing to smaller sample.

Key Molecule: Chloroquine resistance transporter (CRT) [3]

• Molecule Alteration: Missense mutation + Chromosome variation; PfCRT p.F145I+p.G353V+p.I218F + Haplotype
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PacBio amplicon sequencing assay; Whole genome sequencing assay
• Experiment for Drug Resistance: Piperaquine susceptibility testing assay
• Mechanism Description: Parasites with the Dd2 haplotype and pfpm2 amplification had significantly greater mean log10-transformed piperaquine IC90 compared to Dd2 parasites without pfpm2 amplification (t test, P =.0079). In parasites with newly emerged PfCRT mutations, mean log10-transformed piperaquine IC90 was not significantly different between parasites with or without pfpm2 amplification.

Key Molecule: Chloroquine resistance transporter (CRT) [6]

• Molecule Alteration: Missense mutation; p.T93S+p.H97Y+p.F145I+p.I218F
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Piperaquine survival assay
• Mechanism Description: The characterization of culture-adapted isolates revealed that the presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification.

Key Molecule: Putative chloroquine resistance transporter (PVCRT) [7]

• Molecule Alteration: Missense mutation; p.C350R
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast strain CH1305; 4932
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: At 300 uM PPQ, C350R/7G8 PfCRT shows a 3.9-fold increased rate of PPQ transport relative to that of 7G8 PfCRT, and F145I/Dd2 PfCRT shows a 2.7-fold increased rate of PPQ transport relative to that of Dd2.

Key Molecule: Chloroquine resistance transporter (CRT) [5]

• Molecule Alteration: Missense mutation; p.C101F
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum asexual blood-stage parasites; 5833
• Experiment for Molecule Alteration: DNA clones asssay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Plasmepsin II (PMII) [3]

• Molecule Alteration: Missense mutation + Chromosome variation; PfCRT p.F145I+p.G353V+p.I218F + pfpm2 Amplification
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PacBio amplicon sequencing assay; Whole genome sequencing assay
• Experiment for Drug Resistance: Piperaquine susceptibility testing assay
• Mechanism Description: Parasites with the Dd2 haplotype and pfpm2 amplification had significantly greater mean log10-transformed piperaquine IC90 compared to Dd2 parasites without pfpm2 amplification (t test, P =.0079). In parasites with newly emerged PfCRT mutations, mean log10-transformed piperaquine IC90 was not significantly different between parasites with or without pfpm2 amplification.

Key Molecule: Plasmepsin II (PMII) [3]

• Molecule Alteration: Chromosome variation; pfpm2 Amplification+Haplotype
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PacBio amplicon sequencing assay; Whole genome sequencing assay
• Experiment for Drug Resistance: Piperaquine susceptibility testing assay
• Mechanism Description: Parasites with the Dd2 haplotype and pfpm2 amplification had significantly greater mean log10-transformed piperaquine IC90 compared to Dd2 parasites without pfpm2 amplification (t test, P?=?.0079).

References

• Ref 1: Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine. Nat Commun. 2018 Aug 17;9(1):3314. doi: 10.1038/s41467-018-05652-0.
• Ref 2: Prevalence of mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, and association with ex vivo susceptibility to common anti-malarial drugs against African Plasmodium falciparum isolates. Malar J. 2020 Jun 5;19(1):201. doi: 10.1186/s12936-020-03281-x.
• Ref 3: Distribution and Temporal Dynamics of Plasmodium falciparum Chloroquine Resistance Transporter Mutations Associated With Piperaquine Resistance in Northern Cambodia. J Infect Dis. 2021 Sep 17;224(6):1077-1085. doi: 10.1093/infdis/jiab055.
• Ref 4: Evolution of Multidrug Resistance in Plasmodium falciparum: a Longitudinal Study of Genetic Resistance Markers in the Greater Mekong Subregion. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0112121. doi: 10.1128/AAC.01121-21. Epub 2021 Sep 13.
• Ref 5: A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine. mBio. 2017 May 9;8(3):e00303-17. doi: 10.1128/mBio.00303-17.
• Ref 6: Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization. Malar J. 2020 Jul 25;19(1):269. doi: 10.1186/s12936-020-03339-w.
• Ref 7: Altered Drug Transport by Plasmodium falciparum Chloroquine Resistance Transporter Isoforms Harboring Mutations Associated with Piperaquine Resistance. Biochemistry. 2020 Jul 14;59(27):2484-2493. doi: 10.1021/acs.biochem.0c00247. Epub 2020 Jul 1.