Biology subjects

Duffey, M.

Publications and source records attributed to Duffey, M..

3 recordsLinked to original sources

bioRxiv2026

Comparing the transmission blocking efficacy of Primaquine and Tafenoquine with in vivo pre-clinical models

The 8-aminoquinoline family are a well-established class of antimalarial drugs containing two clinically relevant analogues, primaquine and tafenoquine. These compounds have two therapeutically significant activities across the plasmodial lifecycle; elimination of Plasmodium vivax hypnozoites as part of a radical cure (relapse prevention), and as prophylactic transmission blocking compounds. Primaquine is currently recommended as a single low (0.25 mg/kg) dose administered with artemisinin-based combination therapy to reduce malarial transmission in areas at high risk of artemisinin partial resistance. Tafenoquine was approved in 2018 for radical cure when co-administered with chloroquine however, its transmission blocking efficacy in humans has not yet been fully evaluated, and direct head-to-head comparisons of transmission-blocking efficacy of primaquine and tafenoquine have not been performed. Given that primaquine and tafenoquine are presumed to have similar mechanisms of action, tafenoquine may have potential use as a transmission blocking intervention. Furthermore, tafenoquine has a substantially longer half-life than primaquine, which could provide a pharmacokinetic advantage if such efficacy is confirmed. However, assessment of 8-aminoquinoline efficacy against the sexual stages of Plasmodium is complicated by the requirement for metabolic activation to generate parasite-reactive species, limiting the utility of in vitro assays. Here, we directly compare the transmission blocking effects of primaquine and tafenoquine using two in vivo preclinical models. We titrate the transmission blocking efficacy of each compound, and evaluate the pharmacokinetics of each compound over time, linking drug exposure to efficacy. The evidence presented here suggests that beyond 24 hours, a single dose of tafenoquine is likely to have more clinically desirable pharmacokinetics, resulting in higher transmission blocking efficacy than primaquine. These findings are observed across multiple models, both in the absence or presence of a partner schizonticide and thus demonstrate a potential advantage of the utilisation of tafenoquine when compared to primaquine.

microbiology↗

bioRxiv2024

An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs

Elimination and eradication of malaria will depend on new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages able to infect the mosquito vector for onward parasite transmission. The identification of molecules active against these quiescent stages is difficult due to the specific biology of gametocyte maturation and challenges linked to their cultivation in vitro. Furthermore, the antimalarial drug development pipeline lacks a suitable animal model for evaluating the transmission-blocking potential of promising lead compounds and preclinical and clinical drug candidates in vivo. Here, we established a transmission-blocking drug discovery and development platform based on transgenic P. falciparum parasites engineered to produce large numbers of pure stage V gametocytes expressing a red-shifted firefly luciferase as reporter for cellular viability. This NF54/iGP1_RE9Hulg8 line facilitated the development of a highly efficient and robust in vitro screening assay for the identification of stage V gametocytocidal compounds. Importantly, by infecting humanized NODscidIL2R{gamma}null mice with pure NF54/iGP1_RE9Hulg8 stage V gametocytes, we also established a preclinical P. falciparum in vivo transmission model. Using whole animal bioluminescence imaging and quantification of gametocyte densities over a period of 14 days, we assessed the gametocyte killing and clearance kinetics in vivo of antimalarial reference drugs as well as five clinical drug candidates and identified markedly different pharmacodynamic response profiles. Furthermore, we successfully integrated this mouse model with mosquito feeding assays and thus firmly established a valuable tool for the systematic in vivo evaluation of gametocytocidal and transmission-blocking drug efficacy. One sentence summaryWe applied robust new assays for gametocytocidal drug discovery and in vivo efficacy testing using a humanized mouse model for malaria transmission

microbiology↗

bioRxiv2022

Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out

A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC50 [≤] 2 {micro}M), rapid speed of action and cell viability in HepG2 cells (IC50 [≥] 10 {micro}M). Following further profiling, 33 compounds were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.

microbiology↗