Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A

Heyner, Maxi; Krull, Jana; Harmrolfs, Kirsten; Rinne, Valtteri; Hokkanen, Juho; Vilaro, Gemma Perez; Díez, Juana; Müller, Rolf; Kröger, Andrea; Sugiyama, Yuichi; Brönstrup, Mark

doi:10.1021/acsptsci.1c00078

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…Moreover, information about measured tissue and plasma concentrations as well as the PD effect fed into in silico models might help to understand PK/PD drivers in a better way. As tissues can be represented with their compartmental (sub-)structures in in silico models, this allows to calculate the PD effect in specific target tissues [ 37 , 38 ]. A first rough estimation of human equivalent doses using the concept of Reagan-Shaw and colleagues [ 39 ] based on the efficacy data from this study shows that 100 mg/kg would be equivalent to 8.1 mg/kg human dose, whereas a dose of 60 mg/kg has a human equivalent dose of 4.9 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

et al. 2022

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Methicillin-resistant Staphylococcus aureus (MRSA) is a World Health Organization’s high priority pathogen organism, with an estimated > 100,000 deaths worldwide in 2019. Thus, there is an unmet medical need for novel and resistance-breaking anti-infectives. The natural product Co-rallopyronin A (CorA), currently in preclinical development for filariasis, is efficacious against MRSA in vitro. In this study, we evaluated the pharmacokinetics of CorA after dosing in mice. Furthermore, we determined compound concentrations in target compartments, such as lung, kidney and thigh tissue, using LC-MS/MS. Based on the pharmacokinetic results, we evaluated the pharmacodynamic profile of CorA using the standard neutropenic thigh and lung infection models. We demonstrate that CorA is effective in both standard pharmacodynamic models. In addition to reaching effective levels in the lung and muscle, CorA was detected at high levels in the thigh bone. The data presented herein encourage the further exploration of the additional CorA indications treatment of MRSA- and methicillin-sensitive S. aureus- (MSSA) related infections.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

et al. 2022

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“…The plasma stability assay, the metabolic stability assay, and the PPB assay were conducted as described previously. − For the HPLC-MS measurements, samples were analyzed using an Agilent 1290 Infinity II HPLC system coupled to an AB Sciex QTrap 6500plus or an AB Sciex Qtrap7500 mass spectrometer. LC conditions were as follows: column: Agilent Zorbax Eclipse Plus C18, 50 × 2.1 mm, 1.8 μm; temperature: 30 °C; injection volume: 5 μL per sample; flow rate: 700 μL min –1 .…”

Section: Methodsmentioning

confidence: 99%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2024

ACS Pharmacol. Transl. Sci.

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Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with K i values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.455 nM, CatS; 9b, 1.76 nM, CatL; 0.512 nM, CatS). The compounds' inhibitory activity against the main protease of SARS-CoV-2 (M pro ) was additionally investigated. Based on the results at CatL, CatS, and M pro , selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC 50 value of 38.4 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.

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“…Statins, a class of HMGCR inhibitors, have been extensively studied to explore their potential in treating dengue fever (Table 1). Soraphen-A, a compound that targets ACC2, demonstrated remarkable efficacy in reducing DENV-2 viremia in infected mice [119]. Orlistat, a FAS inhibitor, exhibited potent antiviral effects by suppressing replication and infection of all DENV serotypes [107].…”

Section: Molecules Targeting Host Factors From Lipid Metabolismmentioning

confidence: 99%

Exploring Host Factors of the Human Metabolism as Promising Targets for Dengue Treatment

Clemente Tavares,

Sales Nascimento,

Germano de Oliveira

et al. 2024

Infectious Diseases

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The absence of specific therapy and the challenges posed by currently available palliative drugs, such as paracetamol, underscore the urgent need for targeting medications against dengue. Extensive research in the field of antiviral therapies has primarily focused on investigating viral proteins as potential targets. However, despite these efforts, finding an effective therapy for dengue fever remains a daunting task. Importantly, like all viruses, Dengue virus relies on human host proteins to enable infection. Recognizing this fact has prompted the consideration of host factors as viable targets for intervention strategies to combat the infection. This chapter aims to provide an overview of host-virus interactions during Dengue virus infection, emphasizing the importance of metabolic pathways, as well as molecular and cellular processes such as lipid metabolism, autophagy, apoptosis, and the immune system, which are critical for virus propagation. The main goal here is to expand the list of human factors that could serve as potential drug targets. Additionally, molecules that interact with these factors are explored for their therapeutic potential. This comprehensive exploration of host-virus interactions lays the groundwork for more effective dengue treatments. The molecules highlighted here hold promise as antiviral agents, and their inclusion in repurposing research could expedite the development of therapies for dengue fever.

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Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A

Cited by 6 publications

References 59 publications

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Exploring Host Factors of the Human Metabolism as Promising Targets for Dengue Treatment

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