Targeting Human Onchocerciasis: Recent Advances Beyond Ivermectin

Sainas, Stefano; Dosio, Franco; Boschi, Donatella; Lolli, Marco Lucio

doi:10.1016/bs.armc.2018.08.001

Cited by 16 publications

(16 citation statements)

References 103 publications

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“…Several new promising drugs for the treatment of onchocerciasis are being tested in clinical trials [ 11 , 12 ], of which moxidectin was shown to reduce and maintain low skin microfilarial density for longer than ivermectin [ 13 ]. Macrofilaricides, currently only in an early phase of development, will be needed to drastically reduce the elimination time of onchocerciasis [ 11 , 12 ]. However, today none of these new drugs are available for mass drug administration programmes.…”

Section: Introductionmentioning

confidence: 99%

Surveillance for Onchocerciasis-Associated Epilepsy and OV16 IgG4 Testing of Children 6–10 Years Old Should Be Used to Identify Areas Where Onchocerciasis Elimination Programs Need Strengthening

Dusabimana

Fodjo

Ndahura³

et al. 2022

Pathogens

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To eliminate onchocerciasis-associated morbidity, it is important to identify areas where there is still high ongoing Onchocerca volvulus transmission. Between 2015 and 2021, door-to-door surveys were conducted in onchocerciasis-endemic villages in Cameroon, the Democratic Republic of Congo (DRC), Nigeria, South Sudan, and Tanzania to determine epilepsy prevalence and incidence, type of epilepsy and ivermectin therapeutic coverage. Moreover, children aged between six and 10 years were tested for anti-Onchocerca antibodies using the Ov16 IgG4 rapid diagnostic test (RDT). A mixed-effect binary logistic regression analysis was used to assess significantly associated variables of Ov16 antibody seroprevalence. A high prevalence and incidence of epilepsy was found to be associated with a high Ov16 antibody seroprevalence among 6–10-year-old children, except in the Logo health zone, DRC. The low Ov16 antibody seroprevalence among young children in the Logo health zone, despite a high prevalence of epilepsy, may be explained by a recent decrease in O. volvulus transmission because of a decline in the Simulium vector population as a result of deforestation. In the Central African Republic, a new focus of O. volvulus transmission was detected based on the high Ov16 IgG4 seropositivity among children and the detecting of nodding syndrome cases, a phenotypic form of onchocerciasis-associated epilepsy (OAE). In conclusion, Ov16 IgG4 RDT testing of 6–10-year-old children is a cheap and rapid method to determine the level of ongoing O. volvulus transmission and to assess, together with surveillance for OAE, the performance of onchocerciasis elimination programs.

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Section: Introductionmentioning

confidence: 99%

Surveillance for Onchocerciasis-Associated Epilepsy and OV16 IgG4 Testing of Children 6–10 Years Old Should Be Used to Identify Areas Where Onchocerciasis Elimination Programs Need Strengthening

Dusabimana

Fodjo

Ndahura³

et al. 2022

Pathogens

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“…The crystal structure of the protein underwent a preparation process that was performed using the Protein Preparation Wizard tool, implemented in Maestro GUI. − Missing hydrogen atoms were added, missing bonds or atoms were fixed, bond orders were assigned, and water molecules were removed. The prediction of protonation states for the protein was accomplished using PROPKA, with the pH set at 7.4. − The docking procedure was validated by performing a self-docking protocol and verifying the correct positing of the cocrystallized ligand. The coordinates of the bound crystallographic ligand were used as the centroid of the grid box.…”

Section: Methodsmentioning

confidence: 99%

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

et al. 2021

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The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase ( h DHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1 , a potent h DHODH inhibitor (IC 50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC 50 = 32.8 nM) superior to brequinar’s phase I/II clinical trial (EC 50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC 50 = 17.3 nM), strong proapoptotic properties (EC 50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC 30 (Jurkat) > 100 μM).

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“…PGM in mammals require the cofactor whereas PGM present in nematodes and bacteria do not [29]. The NfPGM is likely the cofactor-dependent PGM type.…”

Section: Plos Onementioning

confidence: 98%

Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba

et al. 2021

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Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain’s frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen’s high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen.

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Targeting Human Onchocerciasis: Recent Advances Beyond Ivermectin

Cited by 16 publications

References 103 publications

Surveillance for Onchocerciasis-Associated Epilepsy and OV16 IgG4 Testing of Children 6–10 Years Old Should Be Used to Identify Areas Where Onchocerciasis Elimination Programs Need Strengthening

Surveillance for Onchocerciasis-Associated Epilepsy and OV16 IgG4 Testing of Children 6–10 Years Old Should Be Used to Identify Areas Where Onchocerciasis Elimination Programs Need Strengthening

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Biphenyl Moiety

Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba

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