Recent Efforts in Drug Discovery and Development for the Treatment of Parasitic Infections

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 September 2024) | Viewed by 3922

Special Issue Editor


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Guest Editor
School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
Interests: drug discovery; parasitology; infectious disease biology; biochemistry; natural products

Special Issue Information

Dear Colleagues,

Diseases caused by parasitic infection currently pose an enormous health and economic burden, especially in low- and middle-income countries, where the impact accounts for 96 million disability-adjusted life years. Although the prevention of disease is a fundamental substratum of public health, state-of-the-art therapeutics are presently needed to support the existing armamentarium of interventions to ensure the achievement of efficient disease control and complement the various elimination strategies for parasitic diseases. Over recent decades, extraordinary progress in drug discovery and development technologies has been made by various researchers, and this has been accompanied by the accumulation of important scientific know-how and capability in the clinical and pharmacological sciences that are currently altering the landscape in different aspects of drug research and development across the disciplines related to drug development to treat parasitic diseases. These advancements notwithstanding, the treatment of parasitic infections is facing several major challenges: the relatively limited number of safe and highly effective antiparasitic drugs, and the emergence and rapid spread of resistant strains of parasites. Nevertheless, parasites possess interesting biology, and through evolution and adaptation have developed fascinating strategies for survival, proliferation and the establishment of infection in their hosts. Recent research efforts have revealed some key molecular and biochemical targets which can be explored in the drug discovery process via a rational approach. Drug discovery is a multidisciplinary approach that cuts across various disciplines including biology and chemistry.

The potential topics of this thematic issue can cover research papers or reviews dealing with:

  • The screening of antiparasitic activity of secondary metabolites and other specific molecules from higher plants and low organisms (fungi, lichens, marine plants, and others) on in vitro parasitic models. Rational approaches to drug discovery focus on molecules interfering with specific molecular targets in parasites (for example, inhibitors of receptors, signaling pathways, proteins of the mitochondrial respiratory chain, antioxidants or other types of enzymes, parasitic microRNAs, etc.).
  • Compounds developed by a medicinal chemistry approach, structure-based drug discovery targeting pathogens, chemically modified molecules using natural motifs, innovative drug formulations, and repurposing of drugs.
  • Validation of the in vitro-detected antiparasitic activities of selected compounds on the experimental diseases using mouse or other models. Evaluation of the immunomodulatory effects on the elevation of drug efficacy.
  • Combination therapy as a means to maintain in vivo the synergistic ratio of the drugs combination by the co-incorporation of both immunomodulatory and chemotherapeutic agents.

Dr. Godwin Unekwuojo Ebiloma
Guest Editor

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Keywords

  • drug discovery
  • parasites
  • infectious diseases
  • chemotherapy
  • biochemical targets
  • molecular targets
  • medicinal chemistry

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Published Papers (2 papers)

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Research

27 pages, 2619 KiB  
Article
FRET Assays for the Identification of C. albicans HSP90-Sba1 and Human HSP90α-p23 Binding Inhibitors
by Philip Kohlmann, Sergey N. Krylov, Pascal Marchand and Joachim Jose
Pharmaceuticals 2024, 17(4), 516; https://doi.org/10.3390/ph17040516 - 17 Apr 2024
Viewed by 1217
Abstract
Heat shock protein 90 (HSP90) is a critical target for anticancer and anti-fungal-infection therapies due to its central role as a molecular chaperone involved in protein folding and activation. In this study, we developed in vitro Förster Resonance Energy Transfer (FRET) assays to [...] Read more.
Heat shock protein 90 (HSP90) is a critical target for anticancer and anti-fungal-infection therapies due to its central role as a molecular chaperone involved in protein folding and activation. In this study, we developed in vitro Förster Resonance Energy Transfer (FRET) assays to characterize the binding of C. albicans HSP90 to its co-chaperone Sba1, as well as that of the homologous human HSP90α to p23. The assay for human HSP90α binding to p23 enables selectivity assessment for compounds aimed to inhibit the binding of C. albicans HSP90 to Sba1 without affecting the physiological activity of human HSP90α. The combination of the two assays is important for antifungal drug development, while the assay for human HSP90α can potentially be used on its own for anticancer drug discovery. Since ATP binding of HSP90 is a prerequisite for HSP90-Sba1/p23 binding, ATP-competitive inhibitors can be identified with the assays. The specificity of binding of fusion protein constructs—HSP90-mNeonGreen (donor) and Sba1-mScarlet-I (acceptor)—to each other in our assay was confirmed via competitive inhibition by both non-labeled Sba1 and known ATP-competitive inhibitors. We utilized the developed assays to characterize the stability of both HSP90–Sba1 and HSP90α–p23 affinity complexes quantitatively. Kd values were determined and assessed for their precision and accuracy using the 95.5% confidence level. For HSP90-Sba1, the precision confidence interval (PCI) was found to be 70–120 (100 ± 20) nM while the accuracy confidence interval (ACI) was 100–130 nM. For HSP90α-p23, PCI was 180–260 (220 ± 40) nM and ACI was 200–270 nM. The developed assays were used to screen a nucleoside-mimetics library of 320 compounds for inhibitory activity against both C. albicans HSP90-Sba1 and human HSP90α-p23 binding. No novel active compounds were identified. Overall, the developed assays exhibited low data variability and robust signal separation, achieving Z factors > 0.5. Full article
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21 pages, 22514 KiB  
Article
Zinc Oxide and Magnesium-Doped Zinc Oxide Nanoparticles Ameliorate Murine Chronic Toxoplasmosis
by Mohamed H. Sarhan, Shatha G. Felemban, Walla Alelwani, Hesham M. Sharaf, Yasmin A. Abd El-Latif, Elsayed Elgazzar, Ahmad M. Kandil, Guillermo Tellez-Isaias and Aya A. Mohamed
Pharmaceuticals 2024, 17(1), 113; https://doi.org/10.3390/ph17010113 - 15 Jan 2024
Cited by 1 | Viewed by 1582
Abstract
Toxoplasma gondii causes a global parasitic disease. Therapeutic options for eradicating toxoplasmosis are limited. In this study, ZnO and Mg-doped ZnO NPs were prepared, and their structural and morphological chrematistics were investigated. The XRD pattern revealed that Mg-doped ZnO NPs have weak crystallinity [...] Read more.
Toxoplasma gondii causes a global parasitic disease. Therapeutic options for eradicating toxoplasmosis are limited. In this study, ZnO and Mg-doped ZnO NPs were prepared, and their structural and morphological chrematistics were investigated. The XRD pattern revealed that Mg-doped ZnO NPs have weak crystallinity and a small crystallite size. FTIR and XPS analyses confirmed the integration of Mg ions into the ZnO framework, producing the high-purity Mg-doped ZnO nanocomposite. TEM micrographs determined the particle size of un-doped ZnO in the range of 29 nm, reduced to 23 nm with Mg2+ replacements. ZnO and Mg-doped ZnO NPs significantly decreased the number of brain cysts (p < 0.05) by 29.30% and 35.08%, respectively, compared to the infected untreated group. The administration of ZnO and Mg-doped ZnO NPs revealed a marked histopathological improvement in the brain, liver, and spleen. Furthermore, ZnO and Mg-doped ZnO NPs reduced P53 expression in the cerebral tissue while inducing CD31 expression, which indicated a protective effect against the infection-induced apoptosis and the restoration of balance between free radicals and antioxidant defense activity. In conclusion, the study proved these nanoparticles have antiparasitic, antiapoptotic, and angiogenetic effects. Being nontoxic compounds, these nanoparticles could be promising adjuvants in treating chronic toxoplasmosis. Full article
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