Synthesis and Evaluation of a Novel Synthetic Phosphocholine Lipid-AZT Conjugate that Double-Targets Wild-Type and Drug Resistant Variants of HIV.

AbstractWe report the development of a lab-on-a-chip system, that facilitates coupled dielectrophoretic detection (DEP-D) and impedimetric counting (IM-C), for investigating drug resistance in K562 and CCRF-CEM leukemia cells without (immuno) labeling. Two IM-C units were placed upstream and downstream of the DEP-D unit for enumeration, respectively, before and after the cells were treated in DEP-D unit, where the difference in cell count gave the total number of trapped cells based on their DEP characteristics. Conductivity of the running buffer was matched the conductivity of cytoplasm of wild type K562 and CCRF-CEM cells. Results showed that DEP responses of drug resistant and wild type K562 cells were statistically discriminative (at p = 0.05 level) at 200 mS/m buffer conductivity and at 8.6 MHz working frequency of DEP-D unit. For CCRF-CEM cells, conductivity and frequency values were 160 mS/m and 6.2 MHz, respectively. Our approach enabled discrimination of resistant cells in a group by setting up a threshold provided by the conductivity of running buffer. Subsequent selection of drug resistant cells can be applied to investigate variations in gene expressions and occurrence of mutations related to drug resistance.

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Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.78.4.1718-1729.2004 ◽

2004 ◽

Vol 78 (4) ◽

pp. 1718-1729 ◽

Cited By ~ 135

Author(s):

Haili Zhang ◽

Yan Zhou ◽

Cecily Alcock ◽

Tara Kiefer ◽

Daphne Monie ◽

...

Keyword(s):

Drug Combination ◽

Wild Type Virus ◽

Replication Capacity ◽

Drug Resistant ◽

Type Virus ◽

Wild Type ◽

Cell Level ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.

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Structural, molecular motions, and free-energy landscape of Leishmania sterol-14α-demethylase wild type and drug resistant mutant: a comparative molecular dynamics study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2018.1461135 ◽

2018 ◽

Vol 37 (6) ◽

pp. 1477-1493 ◽

Cited By ~ 8

Author(s):

Saravanan Vijayakumar ◽

Pradeep Das

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Energy Landscape ◽

Resistant Mutant ◽

Free Energy Landscape ◽

Drug Resistant ◽

Molecular Motions ◽

Wild Type ◽

Drug Resistant Mutant

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In silico drug repurposing of FDA-approved drugs to predict new inhibitors for drug resistant T315I mutant and wild-type BCR-ABL1: A virtual screening and molecular dynamics study

Journal of Molecular Graphics and Modelling ◽

10.1016/j.jmgm.2017.04.005 ◽

2017 ◽

Vol 74 ◽

pp. 234-240 ◽

Cited By ~ 7

Author(s):

Farzin Sohraby ◽

Milad Bagheri ◽

Masoud Aliyar ◽

Hassan Aryapour

Keyword(s):

Molecular Dynamics ◽

Virtual Screening ◽

In Silico ◽

Drug Repurposing ◽

Drug Resistant ◽

Wild Type ◽

Approved Drugs ◽

Fda Approved Drugs

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PO-490 Treatment of P53 wild-type cells with P53-inducer idasanutlin® (RG7388) generates stable drug-resistant clones

10.1136/esmoopen-2018-eacr25.507 ◽

2018 ◽

Author(s):

J Kocik ◽

M Rak ◽

T Holak ◽

L Skalniak

Keyword(s):

Drug Resistant ◽

Wild Type

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Interactions Between Antenatal Sulfadoxine-Pyrimethamine, Drug-Resistant Plasmodium falciparum Parasites, and Delivery Outcomes in Malawi

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa145 ◽

2020 ◽

Vol 222 (4) ◽

pp. 661-669 ◽

Cited By ~ 2

Author(s):

Steve M Taylor ◽

Brandt Levitt ◽

Betsy Freedman ◽

Mwayiwawo Madanitsa ◽

Kyaw-Lay Thwai ◽

...

Keyword(s):

Birth Weight ◽

Preventive Therapy ◽

Sub Saharan Africa ◽

Drug Resistant ◽

Wild Type ◽

Resistance Marker ◽

Chain Reaction ◽

Delivery Outcomes ◽

Polymerase Chain ◽

Sub Saharan

Abstract Background Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP recipients. Methods We measured SP-resistance allele frequencies in Malawian women participating in a trial comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped polymerase chain reaction-detected parasites using deep sequencing of SP-resistance alleles. Results Among 125 placental infections, A581G-bearing parasites were associated with reduced birth weight (mean difference [MD], 252 g; 95% confidence interval [CI], 46–457; P = .017). Relative to ISTp, IPTp-SP was associated with higher birth weights in women with wild-type parasites (MD, 116 g; 95% CI, −40 to 272; P = .142) and lower birth weights in women with A581G-bearing parasites (MD, 192 g; 95% CI, −264 to 648; P = .385) (Pinteraction = .033). Similar associations were noted on gestational age (Pinteraction = .075). Amongst only IPTp-SP recipients, relative to women who last received SP > 4 weeks before delivery, recent SP receipt was associated with lower birth weight in women with wild-type parasites (MD, 118 g; 95% CI, −376 to 139; P = .361) and higher birth weight in women with A581G-bearing parasites (MD, 783 g; 95% CI, −20 to 1586; P = .054) (Pinteraction = .005). Conclusions The effectiveness in birth weight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP. ISRCTN Registry www.isrctn.com/ISRCTN69800930.

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