Biology subjects

Duan, C.

Publications and source records attributed to Duan, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Elevated levels of intracellular RNA lariats suppress the antiviral response

Recent studies report the genetic loss of the lariat debranching enzyme (DBR1) activity increases susceptibility to viral infection. Here, we show that more than 25% of human introns contain large hairpin structures created by the folding of two Alu elements inserted in opposite orientation. In wildtype cells, this large reservoir of endogenous dsRNA is efficiently degraded. In DBR1-null cells, lariats accumulate in the cytosol and dsRNA becomes enriched. We demonstrate how the chronic exposure to these lariats attenuates the dsRNA sensors, reducing the response of the MDA5, RIG-I, RNase L and PKR sensing pathways. We observe evidence for both attenuation and endogenous dsRNA in anti-viral response and viral evasion. Lariats are transiently elevated during infection (e.g. HSV-1, influenza, KSHV). The HSV-1 genome expresses multiple, stable lariats that may attenuate dsRNA sensors during latency. HIGHLIGHTSO_LIIntronic inverted repeat Alu elements constitute largest source of endogenous dsRNA. C_LIO_LIIn the absence of DBR1, lariats accumulate in the cytoplasm and form dsRNA. C_LIO_LIChronic exposure to endogenous dsRNA in a DBR1-depleted environment desensitizes the dsRNA sensing pathway. C_LIO_LIICP0 intron 1 of HSV-1 has a highly-structured stable lariat. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/627371v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@3698bborg.highwire.dtl.DTLVardef@654727org.highwire.dtl.DTLVardef@1229245org.highwire.dtl.DTLVardef@b10622_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Sugar-rich foods exacerbate antibiotic-induced microbiome injury

Intestinal microbiota composition is implicated in several diseases; understanding the factors that influence it are key to elucidating host-commensal interactions and to designing microbiome-targeted therapies. We quantified how diet influences microbiome dynamics in hospitalized patients. We recorded 9,419 meals consumed by 173 patients undergoing hematopoietic cell transplantation and profiled the microbiome in 1,009 longitudinally collected stool samples from 158 of them. Caloric intake was correlated with fecal microbiota diversity. Bayesian inference revealed associations between intake of sweets or sugars during antibiotic exposure with microbiome disruption, as assessed by low diversity or expansion of the pathobiont Enterococcus. We validated this observation experimentally, finding that sucrose exacerbated antibiotic-induced Enterococcus expansion in mice. Taken together, our results suggest that avoiding sugar-rich foods during antibiotic treatment may reduce microbiome injury. One Sentence SummaryAnalyses of hematopoietic cell transplant patients and of mice uncover links between foods and microbiome disruption.

microbiology↗

bioRxiv2024

Sox10 is required for systemic initiation of bone mineralization

Heterozygous variants in the gene encoding the SOX10 transcription factor cause congenital syndromes affecting pigmentation, digestion, hearing, and neural function. Most of these symptoms are attributable to failed differentiation and loss of neural crest cells. Extensive research on mouse and zebrafish models has confirmed that Sox10 is essential for most non-skeletal crest derivatives, but seemingly dispensable for skeletal development. We challenge that concept here by revealing a novel requirement for Sox10 in skeletal mineralization. Neither neural crest- nor mesoderm-derived bones initiate mineralization on time in zebrafish sox10 mutants, despite normal osteoblast differentiation and matrix production. We show that mutants are deficient in the ionocyte subpopulation tasked with taking up calcium from the environment through the Trpv6 epithelial calcium channel, leading to a severe calcium deficit that explains the lack of mineralization. As these ionocytes do not derive from a sox10+ lineage, we hypothesized that the primary defect instead resides in a separate organ that regulates ionocyte numbers or calcium uptake at a systemic level. Screening of the endocrine hormones known to regulate calcium homeostasis in adult vertebrates revealed significantly elevated levels of stanniocalcin (Stc1a), an anti-hypercalcemic hormone, in larval sox10 mutants. Previous studies demonstrated that Stc1a inhibits calcium uptake in fish by repressing trpv6 expression and blocking proliferation of Trpv6+ ionocytes. Our epistasis assays indicate that excess Stc1a is the proximate cause of the calcium deficit in sox10 mutants. Lineage tracing shows that the pronephros-derived glands that synthesize Stc1a interact with sox10+ neural crest-derived cells, and that the latter are missing in mutants. We conclude that a subpopulation of Sox10+ neural crest non-cell-autonomously limit Stc1a production to allow the inaugural wave of calcium uptake necessary for the initiation of bone mineralization.

developmental biology↗

bioRxiv2024

Personalized composite scaffolds for accelerated cell- and growth factor-free craniofacial bone regeneration

Approaches to regenerating bone often rely on the integration of biomaterials and biological signals in the form of cells or cytokines. However, from a translational point of view, these approaches face challenges due to the sourcing and quality of the biologic, unpredictable immune responses, complex regulatory paths, and high costs. We describe a simple manufacturing process and a material-centric 3D-printed composite scaffold system (CSS) that offers distinct advantages for clinical translation. The CSS comprises a 3D-printed porous polydiolcitrate-hydroxyapatite composite elastomer infused with a polydiolcitrate-graphene oxide hydrogel composite. Using a continuous liquid interface production 3D printer, we fabricate a precise porous ceramic scaffold with 60% hydroxyapatite content resembling natural bone. The resulting scaffold integrates with a thermoresponsive hydrogel composite, customizable in situ to fit the defect. This hybrid phasic porous CSS mimics the bone microenvironment (inorganic and organic) while allowing independent control of each material phase (rigid and soft). The CSS stimulates osteogenic differentiation in vitro and in vivo. Moreover, it promotes M2 polarization and blood vessel ingrowth, which are crucial for supporting bone formation. Our comprehensive micro-CT analysis revealed that within 4 weeks in a critical-size defect model, the CSS accelerated ECM deposition (8-fold) and mineralized osteoid (69-fold) compared to the untreated. Our material-centric approach delivers impressive osteogenic properties and streamlined manufacturing advantages, potentially expediting clinical application for bone reconstruction surgeries.

bioengineering↗

bioRxiv2024

IL-1beta-induced epithelial cell and fibroblast transdifferentiation fuels neutrophil recruitment in chronic rhinosinusitis with nasal polyps

Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identified two IL-1 signaling-induced cell subsets--LY6D+ club cells and IDO1+ fibroblasts--that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1{beta}, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D+ club cells and IDO1+ fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1{beta} activity with a receptor antagonist significantly reduced the numbers of LY6D+ club cells and IDO1+ fibroblasts and mitigated nasal inflammation. This study reveals the roles of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.

immunology↗

bioRxiv2023

RAG-17: A Novel siRNA Conjugate Demonstrating Efficacy in Late-Stage Treatment of SOD1G93A ALS mice

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkable in vitro stability and target specificity with minimal immunostimulation. In vivo studies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1G93A ALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.

pharmacology and toxicology↗

bioRxiv2023

3D-printed, Citrate-based Bioresorbable Vascular Scaffolds for Coronary Artery Angioplasty

Fully bioresorbable vascular scaffolds (BVSs) were designed to overcome the limitations of metallic drug-eluting stents (DESs). However, current polymer-based BVSs, such as Abbotts Absorb, the only US FDA-approved BVS, struggle with increased strut thickness (150 m for Absorb) and exacerbated tissue inflammation, leading to inferior clinical performance compared to metallic DESs. Here we develop a drug-eluting BVS (DE-BVS) through the innovative use of photopolymerizable, citrate-based materials and high-precision additive manufacturing process. Bare BVS with a clinically relevant strut thickness of 62 m can be produced in a high-throughput manner, i.e. one BVS per minute. By modulating the coating polymer and structure, we achieve a controlled release of anti-restenosis drug of everolimus from DE-BVSs. We show the mechanical competence of DE-BVS and the successful deployment in swine coronary arteries using a custom-built balloon catheter delivery system. We further demonstrate that BVS and DE-BVS remain safe and effective to keep the vessel patency, induce limited inflammation, and facilitate the recovery of smooth muscle and endothelial tissues over 28 days implantation in swine coronary arteries. All these evaluated pre-clinical performances are largely comparable to the commercial XIENCE DES (Abbott Vascular).

bioengineering↗

bioRxiv2023

ChEC-seq2: an improved Chromatin Endogenous Cleavage sequencing method and bioinformatic analysis pipeline for mapping in vivo protein-DNA interactions

Defining the in vivo DNA binding specificity of transcription factors (TFs) has relied nearly exclusively on chromatin immunoprecipitation (ChIP). While ChIP reveals TF binding patterns, its resolution is low. Higher resolution methods employing nucleases such as ChIP-exo, chromatin endogenous cleavage (ChEC-seq) and CUT&RUN resolve both TF occupancy and binding site protection. ChEC-seq, in which an endogenous TF is fused to micrococcal nuclease, requires neither fixation nor antibodies. However, the specificity of DNA cleavage during ChEC has been suggested to be lower than the specificity of the peaks identified by ChIP or ChIP-exo, perhaps reflecting non-specific binding of transcription factors to DNA. We have simplified the ChEC-seq protocol to minimize nuclease digestion while increasing the yield of cleaved DNA. ChEC-seq2 cleavage patterns were highly reproducible between replicates and with published ChEC-seq data. Combined with DoubleChEC, a new bioinformatic pipeline that removes non-specific cleavage sites, ChEC-seq2 identified high-confidence cleavage sites for three different yeast TFs that are strongly enriched for their known binding sites and adjacent to known target genes.

genomics↗

bioRxiv2023

Spotted fever group rickettsiae were the dominant pathogens in parasitic Rhipicephalus microplus in Yunnan Province, China*

ObjectiveTicks as ectoparasites might carry many pathogens and transmitted to their hosts through blood feeding. Human might have the opportunity to be bite by ticks, therefore getting various tick-borne pathogens. Distribution of bacterium flora in ticks plays an essential role in mapping and preventing local tick-borne diseases. Our aim is to map the distribution of bacterium flora and identify the main tick-borne pathogens in dominant tick species in grazing areas of Yunnan province. MethodsV3-V4 region of 16S rRNA amplifier sequencing was used to analyze and study the tick-borne pathogens in Rh. Microplus. The prevalence survey on B.burgdorferi s.l., B. miyamotoi, E. chaffeensis, A. phagocytophilum, Coxiella burnetii and Spotted fever group rickettsiae was carried out via PCR. ResultsThe results showed 105 genus and 117 species were detected in 50 (24 in Yunpan, 26 in Menghun) ticks. Pathogen prevalence testing showed the ticks were positive for B.burgdorferi s.l.(9/50, 18%), Spotted fever group rickettsiae (35/50, 70%), and A.phagocytophilum (1/50, 2%). ConclusionIn our analysis, Spotted fever group rickettsiae were the dominant pathogens in these areas. At the same time, we found that v3-v4 high-throughput sequencing of 16S rRNA gene is not sensitive to identify species for certain bacteria(such as B. burgdorferi s.l.). More accurate and comprehensive analysis would be necessary for detecting tick bacterium flora.

molecular biology↗

bioRxiv2023

Cell type deconvolution of bulk blood RNA-Seq to reveal biological insights of neuropsychiatric disorders

Genome-wide association studies (GWAS) have uncovered susceptibility loci associated with psychiatric disorders like bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome with unknown causal mechanisms of the link between genetic variation and disease risk. Expression quantitative trait loci (eQTL) analysis of bulk tissue is a common approach to decipher underlying mechanisms, though this can obscure cell-type specific signals thus masking trait-relevant mechanisms. While single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell type proportions and cell type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-Seq from 1,730 samples derived from whole blood in a cohort ascertained for individuals with BP and SCZ this study estimated cell type proportions and their relation with disease status and medication. We found between 2,875 and 4,629 eGenes for each cell type, including 1,211 eGenes that are not found using bulk expression alone. We performed a colocalization test between cell type eQTLs and various traits and identified hundreds of associations between cell type eQTLs and GWAS loci that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on cell type expression regulation and found examples of genes that are differentially regulated dependent on lithium use. Our study suggests that computational methods can be applied to large bulk RNA-Seq datasets of non-brain tissue to identify disease-relevant, cell type specific biology of psychiatric disorders and psychiatric medication.

genomics↗

bioRxiv2023

FK506 binding protein 5 regulates cell quiescence-proliferation decision in zebrafish epithelium

The cell proliferation-quiescence decision plays fundamental roles in tissue formation and regeneration, and its dysregulation can lead to human diseases. In this study, we performed transcriptomics and genetic analyses using a zebrafish model to identify pathways and genes involved in epithelial cell quiescence-proliferation regulation. In this in vivo model, a population of GFP-labeled epithelial cells known as ionocytes were induced to reenter the cell cycle by a physiological stress. Transcriptomics analysis identified 1168 genes up-regulated and 996 genes down-regulated in the reactivated cells. GO and KEGG pathway analyses revealed that genes involved in transcription regulation, cell cycle, Foxo signaling, and Wnt signaling pathway are enriched among the up-regulated genes, while those involved in ion transport, cell adhesion, and oxidation-reduction are enriched among the down-regulated genes. Among the top up-regulated genes is FK506 binding protein 5 (Fkbp5), a member of the conserved immunophilin family. CRISPR/Cas9-mediated Fkbp5 deletion abolished ionocyte reactivation and proliferation. Pharmacological inhibition of Fkbp5 had similar effects. Further analyses showed that genetic deletion and inhibition of Fkbp5 impaired Akt signaling. Forced expression of a constitutively active form of Akt rescued the defects caused by Fkbp5 inhibition. These results uncover a previously unrecognized role of Fbkp5 in regulating the quiescence-proliferation decision via Akt signaling. Impact StatementTranscriptomic and genetic deletion studies unravel a new role of Fkbp5 in promoting cell reactivation via Akt signaling. HighlightsO_LITranscriptomic analysis reveals several molecular pathways altered during epithelial cell quiescence-proliferation transition. C_LIO_LIFkbp5 is highly up-regulated in reactivated and dividing cells. C_LIO_LIFkbp5 promotes epithelial cell reactivation and proliferation via Akt signaling. C_LI

cell biology↗

bioRxiv2023

Local administration of a novel siRNA modality into the CNS extends survival and improves motor function in the SOD1G93A mouse model for ALS

Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of ALS caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing with historically superior potency in which short interfering RNAs (siRNAs) guide the RNA-induced silencing complex (RISC) to cleave complementary transcripts. However, delivery to extrahepatic tissues like the central nerve system (CNS) has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 (hSOD1) in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enables durable and potent activity in CNS tissues. Local delivery via intracerebroventricular (ICV) or intrathecal (IT) injection into SOD1G93A mice delayed disease progression and extended animal survival with superior efficacy compared to an ASO compound resembling Tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (i.e., siRNA-ACO) represents a novel modality for delivery of RNAi to the CNS in which we aim to pursue ALS as an exemplary indication for clinical development.

cell biology↗

bioRxiv2022

ROS signaling-induced mitochondrial Sgk1 regulates epithelial cell plasticity

Many types of differentiated cells can reenter the cell cycle upon injury or stress. The mechanisms underlying this cell plasticity are still poorly understood. Here we investigated cell plasticity regulation using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. We observed a robust and sustained increase in mitochondrial membrane potential in reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Deletion and inhibition of Sgk1 in zebrafish abolished cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, Sgk1 coordinates mitochondrial activity with ATP synthesis by modulating F1Fo-ATP synthase phosphorylation. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal. One sentence highlightThis study reports a new intramitochondrial signaling loop regulating epithelial cell renewal.

cell biology↗

bioRxiv2022

The TaxUMAP atlas: efficient display of large clinical microbiome data reveals ecological competition involved in protection against bacteremia

The microbiome is associated with health and disease, but causal effects are hard to quantify-- especially in humans where controlled experiments are nearly impossible. Akin to natural experiments, closely monitored patients offer an alternative to characterize microbiome effects. We present TaxUMAP, a taxonomically-informed visualization method to effectively display diverse microbiome states. TaxUMAP charts a microbiome atlas from 1,870 cancer patients as they progress through therapy-induced perturbations, and quantifies the microbiome contribution to patients risk for life-threatening bacteremia. We find that the lowest diversity states (gut dominations) that follow antibiotic treatments are stable, and that diverse communities harbor more diverse antimicrobial resistance genes than dominations. We reveal that certain Klebsiella species are associated with reduced risk for bacteremia, an effect driven by bacterial competition that we validate experimentally in vitro and in vivo. TaxUMAP effectively maps longitudinal microbiome data that can facilitate research into causal microbiome effects on human health. HIGHLIGHTSO_LITaxUMAP charts an atlas of patients microbiome states and their clinical context to reveal new causal effects. C_LIO_LIAntibiotics deplete the biodiversity and reduce the number of different antimicrobial resistance genes in the gut microbiome. C_LIO_LICertain Klebsiella species are associated with lower risk of bacteremia by other gut-borne pathogens. C_LIO_LIThese Klebsiella outcompete other gram-negative pathogens in vivo. C_LI

microbiology↗

bioRxiv2021

Powerful eQTL mapping through low coverage RNA sequencing

Mapping genetic variants that regulate gene expression (eQTL mapping) in large-scale RNA sequencing (RNA-seq) studies is often employed to understand functional consequences of regulatory variants. However, the high cost of RNA-Seq limits sample size, sequencing depth, and therefore, discovery power. In this work, we demonstrate that, given a fixed budget, eQTL discovery power can be increased by lowering the sequencing depth per sample and increasing the number of individuals sequenced in the assay. We perform RNA-Seq of whole blood tissue across 1490 individuals at low-coverage (5.9 million reads/sample) and show that the effective power is higher than that of an RNA-Seq study of 570 individuals at high-coverage (13.9 million reads/sample). Next, we leverage synthetic datasets derived from real RNA-Seq data to explore the interplay of coverage and number individuals in eQTL studies, and show that a 10-fold reduction in coverage leads to only a 2.5-fold reduction in statistical power. Our study suggests that lowering coverage while increasing the number of individuals is an effective approach to increase discovery power in RNA-Seq studies.

genomics↗

bioRxiv2020

Insights into the mechanism of bovine spermiogenesis based on comparative transcriptomic studies

To reduce the reproductive loss caused by semen quality and provide theoretical guidance for the eradication of human male infertility, differential analysis of the bovine transcriptome among round spermatids, elongated spermatids, and epididymal sperm was carried out with the reference of the mouse transcriptome, and the homology trends of gene expression to the mouse were also analysed. First, to explore the physiological mechanism of spermiogenesis that profoundly affects semen quality, homological trends of differential genes were compared during spermiogenesis in dairy cattle and mice. Next, the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction network (PPI network), and bioinformatics analysis uncovered the regulation network of acrosome formation during the transition from round to elongated spermatids. In addition, processes that regulate gene expression during spermiogenesis from elongated spermatid to epididymal sperm, such as ubiquitination, acetylation, deacetylation, glycosylation, and the functional gene ART3 may play an important role during spermiogenesis. Therefore, its localisation in the seminiferous tubule was investigated by immunofluorescent analysis, and its structure and function were also predicted. This study provides important data for revealing the mystery of life during spermiogenesis resulting from acrosome formation, histone replacement, and the fine regulation of gene expression.

bioinformatics↗

bioRxiv2020

Stanniocalcin 1a is a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca2+ uptake

The mechanisms governing cell quiescence-proliferation balance are poorly defined. Using a zebrafish model, here we report that Stc1a, a glycoprotein known as a hypocalcemic hormone, not only inhibits epithelial calcium uptake but also functions as a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance. Among the 4 stc genes, only the stc1a expression is [Ca2+]-dependent. Genetic deletion of stc1a, but not stc2b, resulted in elevated body Ca2+ contents, ectopic Ca2+ deposit, body swelling, and premature death. Reducing epithelial calcium channel Trpv6-mediated Ca2+ uptake alleviated these phenotypes. Loss of Stc1a also promoted quiescent epithelial cells to re-enter the cell cycle. This action was accompanied by local IGF signaling activation and increased expression in papp-aa, a zinc metalloproteinase degrading Igfbp5a. Genetic deletion of papp-aa or igfbp5a abolished the elevated epithelial cell reactivation in stc1a-/- mutants. Likewise, inhibition of IGF1 receptor, PI3 kinase, Akt, and Tor signaling abolished epithelial cell reactivation. These results reveal that Stc1a plays dual roles in regulating epithelial calcium uptake and cell quiescence-proliferation balance and implicate Trpv6 and Papp-aa-Igfbp5a-IGF signaling in these functions.

developmental biology↗

bioRxiv2020

Computationally Guided Design of BCR-ABL Tyrosine Kinase Inhibitors

BCR-ABL tyrosine kinase inhibitors (TKI) are used to treat the chronic myeloid leukemia (CML). Many TKI have been developed as the primary treatment to the CML. Imatinib, a first generation TKI, directly targets BCR-ABL with effective results. As the disease becomes more advanced, patients start to develop resistance to imatinib. Due to this effect it is necessary to generate novel treatments for advanced stage CML. Computational tools can predict new drug candidates to target BCR-ABL. We have designed two new drug candidates with different levels of modification, based on the predicted structure activity relationships with BCR-ABL. These new drug candidates are predicted to have better binding affinities with BCR-ABL than imatinib, which can be more potent treatments of the disease.

pharmacology and toxicology↗