Potential therapeutic approaches for a sleeping pathogen: tuberculosis a case for bioinorganic chemistry

Sousa, Eduardo Henrique Silva; Diógenes, Izaura C.N.; Lopes, Luiz Gonzaga de França; Moura, José J. G.

doi:10.1007/s00775-020-01803-1

Cited by 7 publications

(4 citation statements)

References 142 publications

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“…These two receptors are then able to phosphorylate DevR, which leads to the upregulation of several genes and several phenotypical changes [160]. The crucial role of this system on initiating the dormancy state supports its importance in the virulence of the pathogen, turning it into a promising potential target for drug discovery [161].…”

Section: Devr/devs/dost Systemmentioning

confidence: 97%

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Campaniço

Harjivan

Warner

et al. 2020

IJMS

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Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery.

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Section: Devr/devs/dost Systemmentioning

confidence: 97%

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Campaniço

Harjivan

Warner

et al. 2020

IJMS

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“…The millenary disease, tuberculosis, is still a major global health issue, causing deaths of over 1 million people around the world [70]. The low number of drugs, emergence of multiple drug-resistant strains and the large reservoir of dormant bacteria within humans have caused a challenge to control and eradicate this disease [71,72]. Almost 20 years ago, a two(three)-component system (DevS-DevR, and later DosT) was identified in M. tuberculosis (Mtb) [73][74][75], which was associated to its virulence.…”

Section: Devs and Dost-a Short Historymentioning

confidence: 99%

“…The O 2 sensor two(three)-component system of M. tuberculosis, DevS/DosT-DevR, has also become an important drug target [72,92,104]. Two laboratories have made efforts to identify new molecules to inhibit this sensing system.…”

Section: Pharmacological Usementioning

confidence: 99%

Heme-Based Gas Sensors in Nature and Their Chemical and Biotechnological Applications

Gondim

Guimarães

Sousa

2022

BioChem

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Sensing is an essential feature of life, where many systems have been developed. Diatomic molecules such as O2, NO and CO exhibit an important role in life, which requires specialized sensors. Among the sensors discovered, heme-based gas sensors compose the largest group with at least eight different families. This large variety of proteins also exhibits many distinct ways of sensing diatomic molecules and promote a response for biological adaptation. Here, we briefly describe a story of two impressive systems of heme-based oxygen sensors, FixL from Rhizobium and DevS(DosS)/DosT from Mycobacterium tuberculosis. Beyond this, we also examined many applications that have emerged. These heme-based gas sensors have been manipulated to function as chemical and biochemical analytical systems to detect small molecules (O2, CO, NO, CN−), fluorophores for imaging and bioanalysis, regulation of processes in synthetic biology and preparation of biocatalysts among others. These exciting features show the robustness of this field and multiple opportunities ahead besides the advances in the fundamental understanding of their molecular functioning.

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“…The research of metal-based compounds for biological applications has received a lot of attention in the past decades [45][46][47] . If initially most of the bioactive metalorganic compounds were conceived as alternatives to anticancer platinum-based drugs [48][49][50] , other pharmacological properties, especially antimicrobial [51][52][53][54][55][56] , and antiparasitic 11,[57][58][59][60][61] activities, further encouraged studies in this area. Ruthenium(II) complexes have shown particularly interesting efficacy against various parasites [62][63][64][65] .…”

Section: Introductionmentioning

confidence: 99%

New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Desiatkina

Mösching

Anghel

et al. 2022

Preprint

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Aiming to generate novel compounds with improved antitoxoplama activity by exploiting the parasite auxotrophies, a library of nucleic base-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates - was synthesized and evaluated. Various structural features as the nucleobase (adenine, uracil, cytosine, thymine, and xanthine) and the linker between the two units were progressively modified. To substantiate the concept, hybrid molecules comprising the diruthenium moiety and other type of pendant molecules were also synthesized and assessed. The use of the CuAAC (copper catalyzed azide-alkyne cycloaddition) approach for the obtainment of conjugates bearing the trithiolato diruthenium scaffold was validated. 37 Compounds (diruthenium conjugates and corresponding intermediates) were assessed in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 μM. In parallel the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. 20 Compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal dose-response studies (IC50, half maximal inhibitory concentration determination) and their toxicity for HFF was assessed at 2.5 μM. Two compounds showing promise for further development were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC50 values of 0.059 and 0.111 μM respectively, significantly lower compared to the standard drug pyrimethamine (IC50 = 0.326 μM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 μM and are candidates as potential treatment options in a suitable in vivo model.

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Potential therapeutic approaches for a sleeping pathogen: tuberculosis a case for bioinorganic chemistry

Cited by 7 publications

References 142 publications

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Heme-Based Gas Sensors in Nature and Their Chemical and Biotechnological Applications

New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

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