scholarly journals Network-driven analysis of human–Plasmodium falciparum interactome: processes for malaria drug discovery and extracting in silico targets

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Francis E. Agamah ◽  
Delesa Damena ◽  
Michelle Skelton ◽  
Anita Ghansah ◽  
Gaston K. Mazandu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Drug Discovery ◽  
Malaria Infection ◽  
Experimental Studies ◽  
Biological Processes ◽  
Potential Drug ◽  
Holistic View ◽  
Human Host ◽  
Host Pathogen

Abstract Background The emergence and spread of malaria drug resistance have resulted in the need to understand disease mechanisms and importantly identify essential targets and potential drug candidates. Malaria infection involves the complex interaction between the host and pathogen, thus, functional interactions between human and Plasmodium falciparum is essential to obtain a holistic view of the genetic architecture of malaria. Several functional interaction studies have extended the understanding of malaria disease and integrating such datasets would provide further insights towards understanding drug resistance and/or genetic resistance/susceptibility, disease pathogenesis, and drug discovery. Methods This study curated and analysed data including pathogen and host selective genes, host and pathogen protein sequence data, protein–protein interaction datasets, and drug data from literature and databases to perform human-host and P. falciparum network-based analysis. An integrative computational framework is presented that was developed and found to be reasonably accurate based on various evaluations, applications, and experimental evidence of outputs produced, from data-driven analysis. Results This approach revealed 8 hub protein targets essential for parasite and human host-directed malaria drug therapy. In a semantic similarity approach, 26 potential repurposable drugs involved in regulating host immune response to inflammatory-driven disorders and/or inhibiting residual malaria infection that can be appropriated for malaria treatment. Further analysis of host–pathogen network shortest paths enabled the prediction of immune-related biological processes and pathways subverted by P. falciparum to increase its within-host survival. Conclusions Host–pathogen network analysis reveals potential drug targets and biological processes and pathways subverted by P. falciparum to enhance its within malaria host survival. The results presented have implications for drug discovery and will inform experimental studies.

scholarly journals Plasmodium falciparum Infection Does Not Affect Human Immunodeficiency Virus Viral Load in Coinfected Rwandan Adults

2014 ◽  
Vol 1 (2) ◽  
Author(s):  
Krishanthi Subramaniam ◽  
Rebeca M. Plank ◽  
Nina Lin ◽  
Adam Goldman-Yassen ◽  
Emil Ivan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Viral Load ◽  
Malaria Infection ◽  
Hiv Transmission ◽  
Falciparum Infection ◽  
Resistance Testing ◽  
Plasmodium Falciparum Infection ◽  
Immunodeficiency Virus

Abstract Background.  Plasmodium falciparum infection has been reported to increase human immunodeficiency virus (HIV) viral load (VL), which can facilitate HIV transmission. We prospectively studied the impact of mild P falciparum coinfection on HIV VL in Rwanda. Methods.  We measured plasma HIV VL at presentation with malaria infection and weekly for 4 weeks after artemether-lumefantrine treatment in Rwandan adults infected with HIV with P falciparum malaria. Regression analyses were used to examine associations between malaria infection and HIV VL changes. Samples with detectable virus underwent genotypic drug-resistance testing. Results.  We enrolled 28 HIV-malaria coinfected patients and observed 27 of them for 5 weeks. Three patients (11%) were newly diagnosed with HIV. Acute P falciparum infection had no significant effect on HIV VL slope over 28 days of follow-up. Ten patients with VL <40 copies/mL at enrollment maintained viral suppression throughout. Seventeen patients had a detectable VL at enrollment including 9 (53%) who reported 100% adherence to ARVs; 3 of these had detectable genotypic drug resistance. Conclusions.  Unlike studies from highly malaria-endemic areas, we did not identify an effect of P falciparum infection on HIV VL; therefore, malaria is not likely to increase HIV-transmission risk in our setting. However, routine HIV testing should be offered to adults presenting with acute malaria in Rwanda. Most importantly, we identified a large percentage of patients with detectable HIV VL despite antiretroviral (ARV) therapy. Some of these patients had HIV genotypic drug resistance. Larger studies are needed to define the prevalence and factors associated with detectable HIV VL in patients prescribed ARVs in Rwanda.

scholarly journals Molecular Epidemiology of Plasmodium falciparum kelch13 Mutations in Senegal Determined by Using Targeted Amplicon Deep Sequencing

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Eldin Talundzic ◽  
Yaye D. Ndiaye ◽  
Awa B. Deme ◽  
Christian Olsen ◽  
Dhruviben S. Patel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Deep Sequencing ◽  
Artemisinin Resistance ◽  
Potential Drug ◽  
Drug Pressure ◽  
Low Frequencies ◽  
Content Type ◽  
Public Health Activity ◽  
Codon Positions

ABSTRACT The emergence of Plasmodium falciparum resistance to artemisinin in Southeast Asia threatens malaria control and elimination activities worldwide. Multiple polymorphisms in the P. falciparum kelch gene found in chromosome 13 (Pfk13) have been associated with artemisinin resistance. Surveillance of potential drug resistance loci within a population that may emerge under increasing drug pressure is an important public health activity. In this context, P. falciparum infections from an observational surveillance study in Senegal were genotyped using targeted amplicon deep sequencing (TADS) for Pfk13 polymorphisms. The results were compared to previously reported Pfk13 polymorphisms from around the world. A total of 22 Pfk13 propeller domain polymorphisms were identified in this study, of which 12 have previously not been reported. Interestingly, of the 10 polymorphisms identified in the present study that were also previously reported, all had a different amino acid substitution at these codon positions. Most of the polymorphisms were present at low frequencies and were confined to single isolates, suggesting they are likely transient polymorphisms that are part of naturally evolving parasite populations. The results of this study underscore the need to identify potential drug resistance loci existing within a population, which may emerge under increasing drug pressure.

A Novel Evolutionary Approach Provides Hope for Limiting Future Drug Resistance in Malaria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 420-420
Author(s):  
Theresa L. Coetzer ◽  
Kubendran Naidoo ◽  
Pierre Durand
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Dihydrofolate Reductase ◽  
Drug Target ◽  
Purifying Selection ◽  
Evolutionary Change ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Novel Approach ◽  
Target Sites

Abstract Malaria continues to be the most lethal protozoan disease of humans and the pathogenesis is fundamentally associated with the infection and hemolysis of red blood cells. Due to the emergence of resistance to most current drugs, there is an urgent need to develop a new generation of anti-parasitic agents. Drug development programs are expensive, long-term endeavors with numerous bottlenecks that exhibit a high rate of attrition. A major concern following the scientific and financial investment in drug discovery is the emergence of drug resistance. This is a well documented problem in malaria, and may be exceedingly rapid, classically demonstrated by pyrimethamine-resistant Plasmodium falciparum malaria. Strategies therefore that identify the most suitable drug target sites to minimize resistance are of major interest. In this study, a novel approach to select such sites based on the evolutionary rate of change is described, using the P. falciparum glycerol kinase (PfGK) as an example. The ratio of non-synonymous (dN) to synonymous (dS) nucleotide substitutions is defined as omega and was used to identify the patterns of evolutionary change at individual codons in the parasite and orthologous human (HsGK) coding sequences. The omega value of a particular codon reflects the evolutionary forces acting on the corresponding amino acid in the protein sequence. Natural selection will retain mutations that are beneficial to the organism and eliminate those that are detrimental. Omega values typically fall into three categories: positive selection (omega>1.0), neutral (omega=1.0), or purifying selection (omega<1.0). In this study, we quantified the relative intensity of selection and introduced the category of extreme purifying selection (omega≤0.1) to identify sites under the most severe evolutionary constraints. We have termed this novel approach to drug target selection “evolutionary patterning” (EP). EP describes the pattern of evolutionary change across a coding sequence, thereby identifying residues that make the most (omega<0.1) and least (omega>1.0) suitable drug target sites based on their potential to produce viable mutations. The EP approach was validated using the P. falciparum dihydrofolate reductase gene. Pyrimethamine targets the dihydrofolate reductase enzyme and five mutations conferring drug resistance have been identified. We hypothesized that none of these mutations would be under extreme purifying selection and our EP investigation confirmed this. EP analysis was thus applied to PfGK, which could be a potential novel drug target. PfGK is annotated as a putative glycerol kinase in the PlasmoDB database and to confirm this predicted function, the full length gene of 1506bp was cloned into a pGEX-4T2 expression vector, the recombinant GST-fusion protein was expressed in E coli and an in vitro assay showed that the enzyme was active and could phosphorylate glycerol. Glycerol-3-phosphate is a multifunctional metabolite that is essential for glycerolipid synthesis and also feeds into glycolysis, highlighting its essential role in parasite metabolism. EP analysis of the PfGK and HsGK genes was conducted separately as part of protozoan and metazoan clades, respectively, and key differences in the evolutionary patterns of the two molecules were identified. These differences were exploited to target the parasite selectively and six potential drug target sites were chosen, which contained residues under extreme purifying selection. To assess the functional and structural significance of these regions, as well as their accessibility to potential therapeutic molecules, they were mapped onto a 3D model of PfGK. This analysis ruled out three of the potential sites, since they were either not essential for enzyme activity or were embedded in the hydrophobic core of the enzyme. In collaboration with medicinal chemists the remaining three potential drug target sites will be used for in silico drug design and docking studies. The strategy of EP and refinement with structural modeling is generic in nature and will limit the development of drug resistance. This represents a significant advance for drug discovery programs in malaria and other infectious diseases.

scholarly journals Historical literature review and molecular analysis of malaria drug resistance markers of Plasmodium falciparum field-isolates from Sudan.

2020 ◽  
Author(s):  
Nouh S. Mohamed ◽  
Hanadi Abdelbagi ◽  
Hussam A. Osman ◽  
Abdallah E. Ahmed ◽  
Alaa M. Yousif ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Frequency Distribution ◽  
Malaria Infection ◽  
Pearson Correlation ◽  
Treatment Protocol ◽  
Public Health Problem ◽  
Historical Literature ◽  
Resistance Markers

Abstract Background Malaria infection is still known to be a worldwide public health problem, especially in tropical and sub-tropical African countries like Sudan. The fight against malaria is still taking place due to many factors. One of these factors is the presence of Plasmodium falciparum drug resistant parasites. This study is aiming at studying the P. falciparum drug resistance markers and analyzing the historical literature on these markers in Sudan. Methods A descriptive cross-sectional healthcare-centers based study conducted in Khartoum state between December 2017 and July 2018. Febrile patients diagnosed with P. falciparum malaria infection were recruited. Two ml blood samples were collected prior to start treatment. Genotyping of the specific point mutations in the P. falciparum genome was done using Sanger sequencing method for the Pfcrt, Pfmdr-1, Pfdhfr, and Pfdhps genes. Data deposited by the worldwide antimalarial resistance network was consulted and the molecular markers previously reported from Sudan were identified, collected, and analyzed to compare between past and present frequency of malaria drug resistance mutations. One-way ANOVA test was used to calculate the least significance of frequency distribution in the molecular markers collected from the previous reports from Sudan in comparison to this study. Pearson correlation was used to investigate the association between the different drug resistance markers. Results Drug molecular markers analysis was successfully done on the 20 P. falciparum isolates. the Pfcrt K76 showed the highest frequency; 16 (80%). Pfcrt 76T was 4 (20%). For the Pfmdr-1 marker, 9 (45%) isolates were carrying the N86 allele and 11 (55%) were 86Y allele. While the Y184F of the Pfmdr-1 showed higher frequency of 184F compared to Y184; 16 (80%) and 4 (20%), respectively. Concerning the double Pfmdr-1 haplotype, NY haplotype was 2 (10%), NF was 7 (35%), YF was 9 (45%), and YY was 2 (10%). In the Pfdhfr , 51I allele showed higher frequency compared to N51; 18 (90%) and 2 (10%), respectively. Whereas for C59R, C59 was 18 (90%), and 59R was 2 (10%). For S108N, 18 (90%) for 108N and 2 (10%) for S108. The triplet haplotype ICN of the Pfdhfr ; was the most frequent haplotype; 16 (80%). Concerning the Pfdhps , all the 20 (100%) isolates were carrying the mutant alleles; 437G and 540E. the Pfdhps haplotype present was the double GE haplotype only. No statistically significant correlation was found for the Pfcrt , Pfmdr-1 , Pfdhfr , and Pfdhps . Historical reports on P. falciparum multidrug resistant collected from 1989 to 2016 showed extreme fluctuation. High prevalence of Pfcrt 76T allele was observed in Khartoum throughout all years of previous studies, while in Gedaref Pfcrt 76T showing increased prevalence each year. All studied genes were showing increase prevalence of the mutant alleles and reduction of the wildtype alleles. In this study, the GE mutant haplotype was prevalent in all the studied samples. Frequency distribution of the Pfcrt K76T and Pfmdr-1 N86Y alleles, Pfmdr-1 ; N86Y and Y184F, Pfdhfr ; N51I and S108N, and Pfdhps ; A437G and K540E double haplotypes was significantly different across the whole years in Sudan. Conclusion This study describes the distribution of P. falciparum multidrug resistance markers throughout Sudan providing a solid baseline data of the status of these markers which could be very useful for the malaria control program not only for establishing surveillance system that monitor the change in and/or the emergence of malaria drug resistance but it will also offer a guidance for the evidence-base decision-making regarding the treatment protocol national and regional wise.

scholarly journals Analyzing the Essential Proteins Set of Plasmodium Falciparum PF3D7 for Novel Drug Targets Identification Against Malaria

2021 ◽  
Author(s):  
Fawad Ali ◽  
Hira Wali ◽  
Saadia Jan ◽  
Muneeba Aslam ◽  
Imtiaz Ahmad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Protein Interactions ◽  
Drug Targets ◽  
Human Life ◽  
Multi Drug Resistance ◽  
Essential Proteins ◽  
Human Host

Abstract Background: Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. P. falciparum is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat.Methods: We retrieved the P. falciparum essential proteins from the recently published studies. Pathogen essential proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analyzed for druggability potential via in silico methods to possibly identify novel therapeutic targets.Results: The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein-protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. Conclusion: The prioritized protein targets may worthy to test in malarial drug discovery program to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

scholarly journals Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fawad Ali ◽  
Hira Wali ◽  
Saadia Jan ◽  
Asad Zia ◽  
Muneeba Aslam ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
Drug Targets ◽  
Human Life ◽  
Multi Drug Resistance ◽  
Essential Proteins ◽  
Human Host

Abstract Background Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat. Methods The P. falciparum essential proteins were retrieved from the recently published studies. These proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analysed for druggability potential via in silico methods to possibly identify novel therapeutic targets. Finally, the PfAp4AH target was prioritized for pharmacophore modelling based virtual screening and molecular docking analyses to identify potent inhibitors from drug-like compounds databases. Results The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not been catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein–protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. The pharmacophore features based virtual screening of Pharmit resource predicted a lead compound i.e. MolPort-045–917-542 as a promising inhibitor of PfAp4AH among prioritized targets. Conclusion The prioritized protein targets may worthy to test in malarial drug discovery programme to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

scholarly journals Modeling the dynamics of Plasmodium falciparum gametocytes in humans during malaria infection

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Pengxing Cao ◽  
Katharine A Collins ◽  
Sophie Zaloumis ◽  
Thanaporn Wattanakul ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clinical Data ◽  
Malaria Infection ◽  
Model Fitting ◽  
Credible Interval ◽  
Dynamics Model ◽  
Bayesian Hierarchical ◽  
Human Host ◽  
Host Infection

Renewed efforts to eliminate malaria have highlighted the potential to interrupt human-to-mosquito transmission — a process mediated by gametocyte kinetics in human hosts. Here we study the in vivo dynamics of Plasmodium falciparum gametocytes by establishing a framework which incorporates improved measurements of parasitemia, a novel gametocyte dynamics model and model fitting using Bayesian hierarchical inference. We found that the model provides an excellent fit to the clinical data from 17 volunteers infected with P. falciparum (3D7 strain) and reliably predicts observed gametocytemia. We estimated the sexual commitment rate and gametocyte sequestration time to be 0.54% (95% credible interval: 0.30–1.00%) per asexual replication cycle and 8.39 (6.54–10.59) days respectively. We used the data-calibrated model to investigate human-to-mosquito transmissibility, providing a method to link within-human host infection kinetics to epidemiological-scale infection and transmission patterns.

Platelet Hypersensitivity in Acute Malaria (Plasmodium falciparum) Infection in Man

1981 ◽  
Vol 46 (02) ◽  
pp. 547-549 ◽  
Author(s):  
E M Essien ◽  
M I Ebhota
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Infection ◽  
Light Transmission ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Wave Pattern ◽  
Falciparum Infection ◽  
Secondary Wave ◽  
Control Subjects ◽  
The Mean

SummaryDuring acute malaria infection, platelets in human platelet-rich plasma are hypersensitive to the addition of ADP between 1.0 uM and 5.0 uM, or adrenaline 0.11 uM as aggregating agents. The mean maximum aggregation amplitude (as % of light transmission) obtained from 8 subjects in response to added ADP (1.0 uM), 39.8 ± 27 (1SD), was significantly greater than the value in 6 controls (5.2±6.7 (1SD); t = 3, 51 P <0.005). A similar pattern of response was obtained with higher ADP concentrations (2.4,4.5 or 5.0 uM) in 22 patients and 20 control subjects (89.9±14.9% vs 77.8±16.5% (1SD) t = 2.45, P <0.02). Addition of 4.5 uM ADP to patient PRP usually evoked only a single aggregation wave (fused primary and secondary waves) while the typical primary and secondary wave pattern was usually obtained from controls.Mean plasma B-thromboglobulin (BTG) concentration in 7 patients (208.3 ± 15.6 ng/ml) was significantly higher than the value in 6 control subjects (59.2±15.7 ng/ml; t = 13.44, P <0.002).

Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

2020 ◽  
Author(s):  
Sanaa Bardaweel
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Antimalarial Drug ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Diabetic Patients ◽  
Potential Drug ◽  
Chemokine Production ◽  
Drug Discovery And Development ◽  
Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

Sign in / Sign up

Export Citation Format

Share Document