IndraLab
Statements
sparser
"Although wide-scale studies that analyzed P . falciparum isolates from numerous sub-Saharan African countries including Ethiopia found no mutations in the parasite’s K13-propeller gene, which is associated with artemisinin resistance in Southeast Asia [ xref , xref ] the threat is clear."
sparser
"These AR strains recrudesce more frequently than artemisinin-sensitive parasites after standard 3-day therapeutic courses with ACTs. xref Genetic mutations of K13-propeller domain are associated with delayed parasite clearance in vivo and reduced susceptibility of the ring-stage parasites in vitro in ring-stage survival assays (RSA). xref , xref PfK13 regional mutations have been often reported in most areas of South East Asia."
sparser
"AR in P. falciparum has been associated with PfK13 polymorphisms, and the K13-propeller domain serves as a molecular marker in the surveillance. xref More than 200 nonsynonymous K13 single-nucleotide polymorphisms have been reported previously, including 11 candidate resistance mutations (P441L, G449A, C469F/Y, A481V, R515K, P527H, N537I/D, G538V, V568G, R622I, A675V, associated with delayed parasite clearance) and 10 validated mutations (F446I, N458Y, M476I, Y493H, R539T, I543T, P553L, R561H, P74L, C580Y, reduced in vitro sensitivity). xref Although K13-propeller mutations are highly predictive of resistance, very little is known about the molecular mechanisms that render P. falciparum insensitive to artemisinins."
sparser
"Mutations in a Kelch domain protein (K13-propeller; PF3D7_1343700) are associated with decreased ART sensitivity in vitro; xref and genetic manipulation of the K13 locus has confirmed a role in the decreased sensitivity phenotype, although other genetic factors also contribute xref ."
sparser
"It has been suggested that Y493H, I543T, R539T, and C580Y mutations in K13-propeller gene are associated with prolonged parasite survival ex vivo; Y493H, R539T, and C580Y mutations are linked to in vivo delayed parasite clearance; and M476I mutation is related to artemisinin tolerance in vitro [ xref , xref , xref , xref ] ."
sparser
"Our observation is consistent with those in previous reports from Kenya [ xref ], Angola [ xref ], Mozambique [ xref ], Senegal [ xref ], Ugandan [ xref ] as well as other areas of Sub-Saharan Africa [ xref ], Caribbean’s Haiti [ xref ], and South Asia’ Bangladesh [ xref ], where the K13-propeller gene mutations associated with artemisinin resistance were absent."
sparser
"These strains included P. falciparum CamWT_C580Y, a K13-propeller mutant associated with increased resistance to artemisinin; Dd2, resistant to chloroquine, pyrimethamine and mefloquine; GB4, resistant to chloroquine; and SB1-A6, resistant to inhibitors of cytochrome bc1 electron transport such as atovaquone xref ."
sparser
"The K13-propeller mutations,140 and the four mutations in the fd, arps10, mdr2, and crt genes,32 have the potential to provide policy makers with a forecast of impending emergence and/or spread of resistance, thus enabling localisation of high-risk regions, and allowing appropriate containment strategies to be implemented."
sparser
"Two important examples of these KELCH proteins are the human intracellular NS1-binding protein (NS1-BP) targeted by NS1 protein of Influenza A virus during infection (Wolff et al. xref ) and the KELCH K13-propeller protein in Plasmodium falciparum where SNPs are associated with artemisinin resistance, which limits the eradication of malaria in areas where these mutations are highly prevalent, for example, Southeast Asia and China (Ménard et al. xref )."
sparser
"Not only is the emergence and spread of ART-resistant isolate in South East Asian regions a matter of concern but also the occurrence of low-frequency candidate mutations in the k13-propeller gene across certain regions of North-Eastern India could draw the state of Odisha's attention."
sparser
"Unfortunately, there is no alternative to the current regimen ACT for the severe uncomplicated malaria and also no significant research has yet been done on K13-propeller polymorphism; hence, it is essential to monitor the efficacy of the Artemisinin derivative through molecular surveillance study in the selected areas of the state during the year 2018."
sparser
"To confirm the activity against asexual stages, PyAz90 was tested against four P. falciparum strains in vitro: the chloroquine-, pyrimethamine-, and mefloquine-resistant
Dd2_R539T (MRA-1255), which also bears a single amino acid change
in the K13-propeller linked to artemisinin resistance xref ; the parental Dd2 line (MRA-156); and the drug-sensitive
lines D6 (MRA-285) and NF54 (MRA-1000)."
sparser
"One member of the superfamily of Kelch-repeat protein, which the K13-propeller protein belongs to, human KEAP1, binds to ubiquitin ligase E3 and a ubiquitination substrate transcription factor at each binding site ( xref ), suggesting that the K13-propeller protein of P. falciparum may also function as an adapter protein that controls the nuclear binding of a stress response transcription factor through ubiquitination and proteosome degradation ( xref )."
sparser
"To search for the molecular target of PyAz90 , the
reference P. falciparum strain Dd2_R539T
(MRA-1255), which bears a single nucleotide substitution
in the K13-propeller gene leading to an R539T amino acid change conferring
more resistance to artemisinin than the parent Dd2 strain, was subjected
to high-pressure intermittent selection with 5 times the initial EC 50 for the selection of a resistant population."
sparser
"However, this success has been threatened by the development of P. falciparum parasites with delayed clearance in response to ACT therapy and their spread throughout Southeast Asia to East India. xref – xref More recently, delayed clearance in response to artemisinin has been reported in parasites from sub-Saharan Africa that lack mutations in the K13-propeller domain protein, which had been associated with delayed clearance by artemisinin-based drugs in southeast Asia. xref , xref The emergence and spread of parasites with delayed clearance to artemisinin treatment makes it imperative to develop new antimalarial drugs against novel therapeutic targets. xref – xref In the current work we utilized a target-based approach to identify small molecule inhibitors that target the malaria parasite purine import pathway."
sparser
"The presence of K13 propeller mutations within Africa, where parasite clearance is generally rapid, suggests that not all K13 propeller mutations are associated with resistance, that secondary loci are involved in resistance and found in Asia but not in Africa thus far, or that the resistance phenotype is masked by high levels of antimalarial immunity."
sparser
"Each patient's parasite isolate was assessed for ex vivo RSA, K13-propeller mutations, pfmdr1 copy number, and pfmdr1 mutations at codons 86, 184, 1034, 1042, and 1246, associated with reduced susceptibility, and 50% inhibitory concentration (IC 50 ) for other antimalarial drugs."
sparser
"In a recent study, Zheng and colleagues [ xref ] selected artemisinin- and piperaquine-resistant P. berghei strains and identified nine mutations in the P. berghei K13-propeller domain with associated prolonged parasite clearance, though none of these mutations are commonly found in the field in P. falciparum ."