作者: Camacho-Moll, María Elena ; Silva-Ramírez, Beatriz ; Peñuelas-Urquides, Katia ; Bermúdez de León, Mario ; Hernández-Luna, Carlos Eduardo ; González-Escalante, Laura Adiene ; Granados-Tristán, Ana Laura

Mycobacteria are microorganisms distributed in the environment worldwide, and some of them, such as Mycobacterium tuberculosis or M. leprae, are pathogenic. The hydrophobic mycobacterial cell envelope has low permeation and bacteria need to export products across their structure. Mycobacteria possess specialized protein secretion systems, such as the Early Secretory Antigenic Target 6 secretion (ESX) system. Five ESX loci have been described in M. tuberculosis, called ESX-1 to ESX-5. The ESX-3 secretion system has been associated with mycobacterial metabolism and growth. The locus of this system is highly conserved across mycobacterial species. Metallo-proteins regulate negative ESX-3 transcription in high conditions of iron and zinc. Moreover, this secretion system is part of an antioxidant regulatory pathway linked to Zinc. EccA3, EccB3, EccC3, EccD3, and EccE3 are components of the ESX-3 secretion machinery, whereas EsxG-EsxH, PE5-PPE4, and PE15-PPE20 are proteins secreted by this system. In addition, EspG3 and MycP3 are complementary proteins involved in transport and proteolysis respectively. This system is associated to mycobacterial virulence by releasing the bacteria from the phagosome and inhibiting endomembrane damage response. Furthermore, components of this system inhibit the host immune response by reducing the recognition of M. tuberculosis-infected cells. The components of the ESX-3 secretion system play a role in drug resistance and cell wall integrity. Moreover, the expression data of this system indicated that external and internal factors affect ESX-3 locus expression. This review provides an overview of new findings on the ESX-3 secretion system, its regulation, expression, and functions.

2023-07-01·European journal of drug metabolism and pharmacokinetics

In Vitro Assessment of the Metabolic Stability of Two Novel Endomorphin-2 Analogs, CYX-5 and CYX-6, in Rat Liver Microsomes.

Letter

作者: Cai, Yunxin ; Ghassabian, Sussan ; Li, Tingyou ; Kuo, Andy ; Imam, Mohammad Zafar ; Smith, Maree T. ; Qin, Yajuan

This study is on the in vitro assessment of the metabolic stability of two novel endomorphin-2 analogs, CYX-5 and CYX-6, in rat liver microsomes.We have recently reported two G-protein-biased endomorphin-2 (EM-2; H-Tyr-Pro-Phe-Phe-NH2) analogs, namely CYX-6 (H-Dmt-Pro-Tmp-Tmp-NH2) and CYX-5 (H-Dmt-Pro-1-Nal-NH2), which showed improved opioid-related adverse-effect profiles in rats relative to morphine.CYX-6 and CYX-5 given by bolus intracerebroventricular administration in rats had superior constipation and respiratory profiles compared with the pos. control morphine.Hence, we designed this study to gain insight into the metabolic stability of these compounds before progressing to a systemic dosing route.Specifically, our aim was to assess the in vitro metabolic stability of CYX-6 and CYX-5 in rat liver microsomes (Sigma Aldrich Pty Ltd, Castle Hill, NSW, Australia) according to the methods described by Pippin et al.The good metabolic stability of the CYX compounds herein affirms their satisfactory stability at supraspinal and spinal sites in the central nervous system after intracerebroventricular administration in rats.The relatively long in vitro half-life of CYX-6 in rat liver microsomes (2.2 h) suggests that it may have a favorable pharmacokinetic profile after systemic administration in rats.

2023-06-01·Pharmacological Reports

CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats

Article

作者: Qin, Yajuan ; Kuo, Andy ; Li, Tingyou ; Cai, Yunxin ; Smith, Maree T ; Ghassabian, Sussan ; Imam, Mohammad Zafar

AbstractBackgroundStrong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by β-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist.MethodsMale Sprague–Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography).ResultsCYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration.ConclusionDespite its lack of recruitment of β-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than β-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.

100 项与 NecroX-5 相关的药物交易

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