ABCB1 p.Ala220Ser
| Predicted by SNAP2: | C: N (82%), D: D (75%), E: D (71%), F: D (63%), G: N (61%), H: D (53%), I: N (57%), K: D (71%), L: D (59%), M: D (59%), N: D (63%), P: D (63%), Q: D (63%), R: D (71%), S: N (93%), T: N (61%), V: N (61%), W: D (75%), Y: D (71%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Chemosensitizers in drug transport mechanisms invo... Curr Drug Targets Infect Disord. 2005 Dec;5(4):411-31. Pradines B, Pages JM, Barbe J
Chemosensitizers in drug transport mechanisms involved in protozoan resistance.
Curr Drug Targets Infect Disord. 2005 Dec;5(4):411-31., [PMID:16535862]
Abstract [show]
The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes. Resistance to quinolines, artemisinin derivatives and arsenicals and expression of an active efflux mechanism are more or less correlated in protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. Various parasite candidate genes have been proposed to be involved in drug resistance, each concerned in membrane transport. Genes encoding membrane glycoproteins, orthologue to the P-glycoproteins identified in MDR human cancer cells, have been described in these resistant pathogens in addition to various membrane proteins involved in drug transport. Several compounds have demonstrated, in the past decade, promising capability to reverse the drug resistance in parasite isolates in vitro, in animal models and for human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and derivatives, and anthracene derivatives. Here, are summarized the molecular bases of antiparasitic resistance emphasizing recent developments with compounds acting on trans-membrane proteins involved in drug efflux or uptake.
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No. Sentence Comment
381 Five mutations in PfCRT, resulting in the amino acid change K76T, M74I, N75E, A220S and R371I, are systematically identified in resistance-reversed Asian, African and Brazilian parasites, which possess the CVIET haplotype [247].
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ABCB1 p.Ala220Ser 16535862:381:78
status: NEW[hide] Association of pfcrt but not pfmdr1 alleles with c... Am J Trop Med Hyg. 2008 Apr;78(4):633-40. Zakeri S, Afsharpad M, Kazemzadeh T, Mehdizadeh K, Shabani A, Djadid ND
Association of pfcrt but not pfmdr1 alleles with chloroquine resistance in Iranian isolates of Plasmodium falciparum.
Am J Trop Med Hyg. 2008 Apr;78(4):633-40., [PMID:18385361]
Abstract [show]
This study was designed to analyze the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) mutations as markers of chloroquine (CQ) resistance in 200 blood samples collected from malaria patients in south-eastern Iran during 2002-2005. Among these, 25 (post-treatment) fulfilled the 28-day follow-up study. A high number of Iranian P. falciparum (97%) strains harbored quadruple mutations at codons 76T, 220S, 326D, and 356L. All post-treatment isolates harbored the mutant allele 76T, but low rates of the mutant allele 86Y (44%) of the pfmdr1 gene were detected. No wild haplotype of pfcrt (72-CVMNKAQNIR-371) was found in post-treatment samples; however, 56% of clinical "failure" samples carried the wild type of pfmdr1 (NYSND). The present results suggest a strong association between pfcrt 76T, but not pfmdr1 86Y mutation and in vivo CQ resistance. Furthermore, we found the CQ resistance-associated SVMNT haplotype, which previously had been seen in South American isolates. Although Iran is located more proximally to Southeast Asia than to South America, no CQ resistance-associated CVIET haplotye has been observed in this region. Therefore, these results were not consistent with the earlier presumed spread of CQR parasites from Southeast Asia to Africa via the Indian subcontinent. In conclusion, P. falciparum mutations associated with resistance to CQ are abundant in south-eastern Iran and this finding strongly supports that CQ as the first line drug is inadequate for treatment of uncomplicated falciparum malaria in Iran.
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No. Sentence Comment
60 Following amplification of the fragments concerned, polymorphisms in the pfcrt and pfmdr1 genes were assessed by the mutation-specific restriction endonuclease digestion to detect single nucleotide polymorphisms (SNPs) in pfcrt at positions K76T, A220S, Q271E, N326S/D, I356T/L, and R371I/T and in pfmdr1 at positions N86Y/H, Y184F, S1034C, N1042D, and D1246Y.45,46 A number of restriction enzymes were used for RFLP of PCR products.45,46 For pfcrt, the PCR products were digested with ApoI, BglI, XmnI, MseI, CaiI, and AFlII to determine the polymorphisms at codons 76, 220, 271, 326, 356, and 371, respectively (detailed information is available on the internet at http://medschool.umaryland.edu/cvd/ nejm2001djimde.asp).
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ABCB1 p.Ala220Ser 18385361:60:247
status: NEW88 Sequence analyses of codons N326S/D TABLE 1 Distribution of pfcrt polymorphisms in pre-and post-treatment samples from Iran based on PCR/RFLP* Pfcrt K76T A220S Q271E N326S/D I356T/L R371I/T Total (%) Pre-treatment K A Q N I/L R 4 (2.3%) T A Q S/D I/L R 1 (0.6%) T S Q S/D I/L R 170 (97.1%) T = 97.7% S = 97% E = 0 S/D = 97.7% I/L = 100% I/T = 0 175 (100) Post-treatment K A Q N I/L R - T A Q S/D I/L R 1 (4%) T S Q S/D I/L R 24 (96%) T = 100% S = 96% E = 0 S/D = 100% I/L = 100% I/T = 0 25 (100%) * Analysis of codon N326S/D by MseI restriction enzyme digestion showed that 97.7% of our samples had either amino acid serine (S) or aspartic acid (D).
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ABCB1 p.Ala220Ser 18385361:88:154
status: NEW[hide] Atorvastatin is a promising partner for antimalari... Antimicrob Agents Chemother. 2009 Jun;53(6):2248-52. Epub 2009 Mar 23. Parquet V, Briolant S, Torrentino-Madamet M, Henry M, Almeras L, Amalvict R, Baret E, Fusai T, Rogier C, Pradines B
Atorvastatin is a promising partner for antimalarial drugs in treatment of Plasmodium falciparum malaria.
Antimicrob Agents Chemother. 2009 Jun;53(6):2248-52. Epub 2009 Mar 23., [PMID:19307369]
Abstract [show]
Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. AVA exposure resulted in the reduced in vitro growth of 22 Plasmodium falciparum strains, with the 50% inhibitory concentrations (IC(50)s) ranging from 2.5 microM to 10.8 microM. A significant positive correlation was found between the strains' responses to AVA and mefloquine (r = 0.553; P = 0.008). We found no correlation between the responses to AVA and to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, or doxycycline. These data could suggest that the mechanism of AVA uptake and/or the mode of action of AVA is different from those for other antimalarial drugs. The IC(50)s for AVA were unrelated to the occurrence of mutations in the transport protein genes involved in quinoline antimalarial drug resistance, such as the P. falciparum crt, mdr1, mrp, and nhe-1 genes. Therefore, AVA can be ruled out as a substrate for the transport proteins (CRT, Pgh1, and MRP) and is not subject to the pH modification induced by the P. falciparum NHE-1 protein. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, and doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a treatment for malaria. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association with drugs known to have activities against the malaria parasite.
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No. Sentence Comment
99 The following mutations were identified in at least one strain: Pfcrt M74I, N75E, K76T, A220S, Q271(E/V), N326S, I356T, and I371R; Pfmrp H191Y and S437A; and Pfmdr1 N86Y, Y184F, S1034C, N1042D, and D1246Y (Table 2).
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ABCB1 p.Ala220Ser 19307369:99:88
status: NEW[hide] Plasmodium falciparum resistance to anti-malarial ... Malar J. 2010 Jan 7;9:8. Marfurt J, Smith TA, Hastings IM, Muller I, Sie A, Oa O, Baisor M, Reeder JC, Beck HP, Genton B
Plasmodium falciparum resistance to anti-malarial drugs in Papua New Guinea: evaluation of a community-based approach for the molecular monitoring of resistance.
Malar J. 2010 Jan 7;9:8., [PMID:20053293]
Abstract [show]
BACKGROUND: Molecular monitoring of parasite resistance has become an important complementary tool in establishing rational anti-malarial drug policies. Community surveys provide a representative sample of the parasite population and can be carried out more rapidly than accrual of samples from clinical cases, but it is not known whether the frequencies of genetic resistance markers in clinical cases differ from those in the overall population, or whether such community surveys can provide good predictions of treatment failure rates. METHODS: Between 2003 and 2005, in vivo drug efficacy of amodiaquine or chloroquine plus sulphadoxine-pyrimethamine was determined at three sites in Papua New Guinea. The genetic drug resistance profile (i.e., 33 single nucleotide polymorphisms in Plasmodium falciparum crt, mdr1, dhfr, dhps, and ATPase6) was concurrently assessed in 639 community samples collected in the catchment areas of the respective health facilities by using a DNA microarray-based method. Mutant allele and haplotype frequencies were determined and their relationship with treatment failure rates at each site in each year was investigated. RESULTS: PCR-corrected in vivo treatment failure rates were between 12% and 28% and varied by site and year with variable longitudinal trends. In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time. Mutant allele frequencies in pfdhfr were moderate and those in pfdhps were low. No mutations were detected in pfATPase6. There was much more variation between sites than temporal, within-site, variation in allele and haplotype frequencies. This variation did not correlate well with treatment failure rates. Allele and haplotype frequencies were very similar in clinical and community samples from the same site. CONCLUSIONS: The relationship between parasite genetics and in vivo treatment failure rate is not straightforward. The frequencies of genetic anti-malarial resistance markers appear to be very similar in community and clinical samples, but cannot be used to make precise predictions of clinical outcome. Thus, indicators based on molecular data have to be considered with caution and interpreted in the local context, especially with regard to prior drug usage and level of pre-existing immunity. Testing community samples for molecular drug resistance markers is a complementary tool that should help decision-making for the best treatment options and appropriate potential alternatives.
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No. Sentence Comment
67 Assessment of SNPs for drug resistant malaria was done for pfmdr1 mutations N86Y, Y184F, S1034C, N1042D and D1246Y, pfcrt mutations K76T, H97Q, T152A, S163R, A220S, Q271E, N326D/S, I356L/T and R371I, pfdhfr mutations A16V, N51I, C59R, S108N/T and I164L, pfdhps mutations S436A, A437G, K540E, A581G and A613T/S, and pfATPase6 mutations S538R, Q574P, A623E, N683K and S769N.
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ABCB1 p.Ala220Ser 20053293:67:158
status: NEW94 Polymorphisms were found in pfmdr1 SNPs N86Y, Y184F and N1042D, pfcrt SNPs K76T, A220S, N326D, I356L and S163R, pfdhfr SNPs C59R and S108N, and pfdhps SNPs A437G and K540E.
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ABCB1 p.Ala220Ser 20053293:94:81
status: NEW99 Frequencies of A220S were highest at the North Coast and lower in Karimui and the Wosera.
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ABCB1 p.Ala220Ser 20053293:99:15
status: NEW121 The most obvious changes were related to the allele frequencies of pfcrt N326D, I356L and A220S, which all decreased over time, as did pfdhpsA437G, while the frequencies of the pfdhfr mutants increased (Table S2, Additional file 2).
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ABCB1 p.Ala220Ser 20053293:121:90
status: NEW[hide] The ABC transporter genes of Plasmodium falciparum... Drug Resist Updat. 2001 Feb;4(1):66-74. Peel SA
The ABC transporter genes of Plasmodium falciparum and drug resistance.
Drug Resist Updat. 2001 Feb;4(1):66-74., [PMID:11512154]
Abstract [show]
The seminal observations that (a) chloroquine-resistant Plasmodium falciparum strains accumulate less drug than more sensitive parasites, and (b) chloroquine resistance could be modulated in vitro by the classic multidrug-resistance (MDR) modulator verapamil, suggested not only that parasite resistance to multiple drugs may be similar to the MDR phenotype described in mammalian cancer cells, but that homologous proteins may be involved. These findings prompted search for MDR-like genes in the parasite. To date, three full-length ABC transporter genes have been isolated from P. falciparum: two P-glycoprotein-like homologues, pfmdr1 and pfmdr2, and a homologue of the yeast GCN20 gene, pfgcn20.
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No. Sentence Comment
35 Sequence analysis of chloroquine resistant parasites from diverse geographic regions (Asia,Africa,SouthAmerica) revealed a polymorphic gene, which in all cases included intra-allelic mutations Lys 76Thr and Ala 220Ser , as well as mutations in two to six additional codons.
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ABCB1 p.Ala220Ser 11512154:35:207
status: NEW