A5056151698- Malaria Research and Control
- Computational Drug Discovery Methods
- Mosquito-borne diseases and control
- Invertebrate Immune Response Mechanisms
- Tuberculosis Research and Epidemiology
- SARS-CoV-2 and COVID-19 Research
- Genital Health and Disease
- Immune Cell Function and Interaction
- Insect Resistance and Genetics
- Research on Leishmaniasis Studies
- Sex work and related issues
- Parasites and Host Interactions
- Influenza Virus Research Studies
- Protein Kinase Regulation and GTPase Signaling
- COVID-19 Clinical Research Studies
- Aquaculture disease management and microbiota
- Synthesis and biological activity
- HIV, TB, and STIs Epidemiology
- Reproductive System and Pregnancy
University of Glasgow
2018-2024
MRC Unit the Gambia
2012-2016
Medical Research Council
2012-2015
Acquired immunity in vertebrates maintains polymorphisms endemic pathogens, leading to identifiable signatures of balancing selection. To comprehensively survey for genes under such selection the human malaria parasite Plasmodium falciparum, we generated paired-end short-read sequences parasites clinical isolates from an Gambian population, which were mapped 3D7 strain reference genome yield high-quality genome-wide coding sequence data 65 isolates. A minority did not map reliably, including...
As indicators of burden malaria have substantially decreased in The Gambia, reaching a pre-elimination status may be attainable. Achieving this goal requires in-depth understanding the current Plasmodium falciparum infection. A nationwide cross-sectional survey was conducted 2012 to determine prevalence P. infection, and describe its heterogeneity associated risk factors. Finger-prick blood samples were collected for microscopy, species-specific PCR haemoglobin measurement. total 9,094...
Targeting parasite's protein kinase Malaria elimination goals are constantly eroded by the challenge of emerging drug and insecticide resistance. Alam et al. have taken established targets—CLK kinases involved in regulation RNA splicing—and investigated how inhibition enzymes blocks completion its complex life cycle. They identified an inhibitor CLK that was 100-fold less active against most closely related human effective at clearing rodent malaria parasites. Not only does this compound...
The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for survival blood stage Plasmodium falciparum. We recently validated as drug target malaria that offers prophylactic, transmission blocking, curative potential. Herein, we describe synthesis our initial hit TCMDC-135051 (1) efforts to establish structure–activity relationship with 7-azaindole-based series. A total 14 analogues were assessed time-resolved fluorescence energy...
The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role natural killer (NK) cell‐derived interferon gamma (IFN‐γ), is becoming increasingly recognised. Recently, it has been shown that IFN‐γ production response P. antigens part regulated by killer‐cell immunoglobulin‐like receptor ( KIR ) genes, and a study from malaria‐exposed Melanesians suggested an association between genotypes susceptibility infection. This prompted us determine...
Abstract The requirement for next generation anti-malarials to be both curative and transmission blockers necessitate the identification of molecular pathways essential viability asexual sexual parasite life stages. Here we identify a selective inhibitor Plasmodium falciparum protein kinase Pf CLK3 which use in combination with chemogenetics, whole genome sequencing transcriptomics validate as druggable target acting at multiple Consistent proposed role regulator RNA splicing, inhibition...
Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by Plasmodium falciparum increasing this number each year. New medicines novel mechanisms of action are, therefore, urgently needed. In work, we solved the cocrystal structure essential malarial kinase PfCLK3 reversible inhibitor TCMDC-135051 (1), enabling design covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in human kinome. Chloroacetamide 4 shows nanomolar...
SARS-CoV-2 viral attachment and entry into host cells is mediated by a direct interaction between spike glycoproteins membrane bound angiotensin-converting enzyme 2 (ACE2). The receptor binding motif (RBM), located within the S1 subunit of protein, incorporates majority known ACE2 contact residues responsible for high affinity associated virulence. Observation existing crystal structures domain (S RBD )–ACE2 interface, combined with peptide array screening, allowed us to define series linear...
The kinase Pf CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for survival blood stage Plasmodium falciparum . We recently validated as drug target malaria that offers prophylactic, transmission blocking curative potential. Herein we describe synthesis our initial hit TCMDC-135051 1 efforts to establish SAR with 7-azaindole-based series. A total 14 analogues were assessed TR-FRET assay against full recombinant protein 10 further parasites 3D7...
<p>The kinase <i>Pf</i>CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for survival blood stage <i>Plasmodium falciparum</i>. We recently validated as drug target malaria that offers prophylactic, transmission blocking curative potential. Herein we describe synthesis our initial hit TCMDC-135051 <b>1</b>and efforts to establish SAR with 7-azaindole-based series. A total 14 analogues were assessed...