Introduction: Conformational diseases are caused by structurally abnormal proteins that cannot fold properly and achieve their native conformation. Misfolded proteins frequently originate from genetic mutations that may lead to loss-of-function diseases involving a variety of structurally diverse proteins including enzymes, ion channels, and membrane receptors. Pharmacoperones are small molecules that cross the cell surface plasma membrane and reach their target proteins within the cell, serving as molecular scaffolds to stabilize the native conformation of misfolded or well-folded but destabilized proteins, to prevent their degradation and promote correct trafficking to their functional site of action. Because of their high specificity toward the target protein, pharmacoperones are currently the focus of intense investigation as therapy for several conformational diseases.
Areas covered: This review summarizes data on the mechanisms leading to protein misfolding and the use of pharmacoperone drugs as an experimental approach to rescue function of distinct misfolded/misrouted proteins associated with a variety of diseases, such as lysosomal storage diseases, channelopathies, and G protein-coupled receptor misfolding diseases.
Expert commentary: The fact that many misfolded proteins may retain function, offers a unique therapeutic opportunity to cure disease by directly correcting misrouting through administering pharmacoperone drugs thereby rescuing function of disease-causing, conformationally abnormal proteins. 相似文献
Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro, it expresses phenotypic resistance to antimicrobial drugs. As the in vivo survival of M. tuberculosis following drug treatment is potentially linked to a biofilm‐like expression of drug tolerance, it is hypothesized that biofilm dispersion should increase antibiotic susceptibility and reduce the duration of the current antibiotic treatment regimen. Previously, we have identified a 2‐aminoimidazole (2‐AI) compound capable of dispersing and inhibiting M. tuberculosis and M. smegmatis biofilms in vitro. Additionally, this compound potentiated the activity of carbenicillin against M. tuberculosis and, to a lesser degree, M. smegmatis. Here, we describe a SAR study on this compound evaluating each derivative for biofilm dispersion and β‐lactam potentiation capabilities against M. smegmatis. This study identified a compound that improved upon the biofilm dispersion capabilities of the lead compound. Interestingly, a different compound was identified with an increased ability to potentiate a subset of β‐lactam antibiotics. These compounds indicate that biofilm dispersion and potentiation capabilities may not be associated. 相似文献
Recently, with rapid changes in the Japanese lifestyle, the clinical condition of patients with multiple chemical sensitivity (MCS) may also have undergone change. Thus, we conducted a new survey for subjective symptoms, ongoing chemical exposures, the prevalence of allergic diseases, and presumed onset/trigger factors in patients with MCS and compared results with those of an old survey from ten years ago.
Methods
The new survey was conducted from 2012 to 2015 and the old survey was independently conducted from 1999 to 2003, meaning it was not a follow-up study. Patients were initially diagnosed by physicians at five medical institutions with MCS specialty outpatient services, with 111 and 103 patients participating in the new and old surveys, respectively. The controls were a general population living in Japan, with 1313 and 2382 participants in the new and old surveys, respectively. Subjective symptoms and ongoing chemical exposure were evaluated using a quick environmental exposure sensitivity inventory. Additionally, from clinical findings recorded by an attending physician, the prevalence of allergic diseases and presumed onset/trigger factors were evaluated. Differences between new and old surveys were analyzed using logistic regression analyses and significance tests.
Results
Compared with ten years ago: (1) Regarding factors affecting patients with ongoing chemical exposures, the proportion of patients affected decreased significantly for two items only (insecticides and second-hand smoke). The proportion of controls showing ongoing exposure to 8 out of 10 items changed significantly. (2) In patients, scores for chemical intolerances, other intolerances, and life impacts increased significantly. (3) In terms of the prevalence of allergic diseases among patients with MCS, bronchial asthma (adjusted odds ratio [AOR]: 5.19), atopic dermatitis (AOR: 3.77), allergic rhinitis (AOR: 5.34), and food allergies (AOR: 2.63) increased significantly, while hay fever (AOR: 0.38) and drug allergies (AOR: 0.40) decreased significantly. (4) With regard to construction and renovation, which was the presumed predominant onset/trigger factor for MCS 10 years ago, this decreased from 68.9% to 35.1%; in contrast, electromagnetic fields (0.0%–26.1%), perfume (0.0%–20.7%), and medical treatment (1.9%–7.2%) increased significantly, confirming the diversification of onset/trigger factors.
Conclusion
Compared to ten years ago, for patients with MCS, an increase in avoidance behavior toward chemical substance exposures, which were presumed to be aggravating factors for symptoms, was confirmed. It has been suggested that the ongoing chemical exposure of the general population in Japan has largely changed. In addition, for patients with MCS, chemical intolerances and life impacts have become severe, the prevalence of the main allergic diseases has increased, and onset/trigger factors have become diversified. 相似文献