Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial

Rodrigues-Junior, Valnês S.; Cintra, Luciana; Machado, Pablo; Dadda, Adílio da Silva; Basso, Luiz Augusto; Mafra, Ana Carolina Cintra Nunes; Campos, Alexandre; Campos, Maria Martha; Santos, Daniel Silas Veras dos

doi:10.1016/j.yrtph.2017.08.015

Cited by 10 publications

(15 citation statements)

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“…Furthermore, toxicity assays revealed a very favorable profile for IQG-607, according to assessment of cell lineages or primary culture cells. This is in accord with previous publications showing a very good safety profile for IQG-607 in mice, rats, and minipigs [ 41 – 43 ]. Noteworthy, IQG-607 did not exhibit genotoxic effects, as revealed by the alkaline comet assay, further reinforcing the favorable toxicological profile of this molecule.…”

Section: Discussionsupporting

confidence: 93%

Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis

et al. 2017

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M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M. tuberculosis, a key component in the FASII system. Here, we aimed to evaluate the inhibitory activity of IQG-607 against promastigote and amastigote forms of Leishmania (Viannia) braziliensis isolated from patients with different clinical forms of L. braziliensis infection, including cutaneous, mucosal and disseminated leishmaniasis. Importantly, IQG-607 inhibited the proliferation of three different isolates of L. braziliensis promastigotes associated with cutaneous, mucosal and disseminated leishmaniasis. The IC50 values for IQG-607 ranged from 32 to 75 μM, for these forms. Additionally, IQG-607 treatment decreased the proliferation of intracellular amastigotes in infected macrophages, after an analysis of the percentage of infected cells and the number of intracellular parasites/100 cells. IQG-607 reduced from 58% to 98% the proliferation of L. braziliensis from cutaneous, mucosal and disseminated strains. Moreover, IQG-607 was also evaluated regarding its potential toxic profile, by using different cell lines. Cell viability of the lineages Vero, HaCat and HepG2 was significantly reduced after incubation with concentrations of IQG-607 higher than 2 mM. Importantly, IQG-607, in a concentration of 1 mM, did not induce DNA damage in HepG2 cells, when compared to the untreated control group. Future studies will confirm the mechanism of action of IQG-607 against L. braziliensis.

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Section: Discussionsupporting

confidence: 93%

Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis

et al. 2017

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“…Another possible explanation involves an intramolecular electron transference mediated by the metal center that would self-activate the INH moiety from IQG-607 inside the host macrophages, thus forming a hypothetical adduct with NADH (4). Despite the extensive characterization of IQG-607 interaction with the InhA enzyme, its activity in mice (5), and its favorable toxicological profile in rats (6) and mini pigs (7), it is still unknown if the compound is active against M. tuberculosis strains carrying mutations in the katG gene, hence our work focused on elucidating the mechanism of resistance of the M. tuberculosis to the compound IQG-607 by employing a genetic approach with a set of different INH-resistant strains.…”

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confidence: 99%

Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis

Abbadi

Villela

Rodrigues-Junior

et al. 2018

Antimicrob Agents Chemother

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IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the gene. The (S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.

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“…For the repeated-dose experiments in minipigs, the administered doses (15, 30, and 65 mg/kg) corresponded to those used in the repeated administration study in rats (Rodrigues-Junior et al, 2017b ). Interestingly, the repeated oral dosing of IQG-607 to minipigs did not cause deaths (Rodrigues-Junior et al, 2017a ), contrary to the observations in rats (Rodrigues-Junior et al, 2017b ). However, in the sub-chronic study, mild adverse effects were observed (Rodrigues-Junior et al, 2017a ).…”

Section: Toxicity Studiesmentioning

confidence: 83%

“…Taking into consideration that toxicological investigations in a non-rodent species are mandatory and that they could predict safety, tolerability and potential adverse and harmful reactions of a drug in humans, IQG-607 was also tested in minipigs, following single and repeated schedules of administration, as recommended by OECD (OECD, 2001 ; Rodrigues-Junior et al, 2017a ). Of importance, minipigs are considered close to humans in terms of anatomy, biochemistry and physiology (Bode et al, 2010 ).…”

Section: Toxicity Studiesmentioning

confidence: 99%

“…Therefore, testing in minipigs is considered predictive of human reactions, bringing a more accurate estimate of harmful effects to humans. A single dose of IQG-607 (220 mg/kg) administered to both male and female minipigs did not cause mortality, morbidity, body weight changes, alteration of food and water consumption, or alterations at necropsy (Rodrigues-Junior et al, 2017a ). It is important to mention that the dose of 220 mg/kg corresponds to the dose of 1,000 mg/kg, for rodents, as calculated based on the body surface area.…”

Section: Toxicity Studiesmentioning

confidence: 99%

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Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

et al. 2018

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The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG-encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2-trans-enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3[FeII(CN)5(INH)]·4H2O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation. HPLC and EPR studies showed that the INH moiety can be oxidized by superoxide or peroxide yielding similar metabolites and isonicotinoyl radical only when associated to IQG-607, thereby supporting redox-mediated drug activation as a possible mechanism of action. However, IQG-607 was shown to inhibit the in vitro activity of both wild-type and INH-resistant mutant InhA enzymes in the absence of KatG activation. IQG-607 given by the oral route to M. tuberculosis-infected mice reduced lung lesions. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. HPLC and voltammetric methods were developed to quantify IQG-607. Pharmacokinetic studies showed short half-life, high clearance, moderate volume of distribution, and low oral bioavailability, which was not altered by feeding. Safety and toxic effects of IQG-607 after acute and 90-day repeated oral administrations in both rats and minipigs showed occurrence of mild to moderate toxic events. Eight multidrug-resistant strains (MDR-TB) were resistant to IQG-607, suggesting an association between katG mutation and increasing MIC values. Whole genome sequencing of three spontaneous IQG-607-resistant strains harbored katG gene mutations. MIC measurements and macrophage infection experiments with a laboratorial strain showed that katG mutation is sufficient to confer resistance to IQG-607 and that the macrophage intracellular environment cannot trigger the self-activation mechanism. Reduced activity of IQG-607 against an M. tuberculosis strain overexpressing S94A InhA mutant protein suggested both the need for KatG activation and InhA as its target. Further efforts are suggested to be pursued toward attempting to translate IQG-607 into a chemotherapeutic agent to treat tuberculosis.

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Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial

Cited by 10 publications

References 12 publications

Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis

Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis

Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

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