RESUMO
Functional inactivation of wild-type p53 is a major trait of cancerous cells. In many cases, such inactivation occurs by either TP53 gene mutations or due to overexpression of p53 binding partners. This review focuses on an overexpressed p53 binding partner called mortalin, a mitochondrial heat shock protein that sequesters both wild-type and mutant p53 in malignant cells due to changes in subcellular localization. Clinical evidence suggests a drastic depletion of the overall survival time of cancer patients with high mortalin expression. Therefore, mortalin-p53 sequestration inhibitors could be game changers in improving overall survival rates. This review explores the consequences of mortalin overexpression and challenges, status and strategies for accelerating drug discovery to suppress mortalin-p53 sequestration.
Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismoRESUMO
Lysophosphatidic acid (LPA) activates six LPA receptors (LPAR1-6) and regulates various cellular activities such as cell proliferation, cytoprotection, and wound healing. Many studies elucidated the pathological outcomes of LPA are due to the alteration in signaling pathways, which include migration and invasion of cancer cells, fibrosis, atherosclerosis, and inflammation. Current pathophysiological research on LPA and its receptors provides a means that LPA receptors are new therapeutic targets for disorders associated with LPA. Various chemical modulators are developed and are under investigation to treat a wide range of pathological complications. This review summarizes the physiological and pathological roles of LPA signaling, development of various LPA modulators, their structural features, patents, and their clinical outcomes.
Assuntos
Lisofosfolipídeos/farmacologia , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Lisofosfolipídeos/química , Lisofosfolipídeos/metabolismo , Estrutura Molecular , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Dengue virus belongs to the class of RNA viruses and subclass of enveloped single-stranded positive-sense RNA virus. It causes dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS), where DHF and DSS are life-threatening. Even though dengue is an age-old disease, it is still a mystery and continues to be a global threat. Numerous attempts have been carried out in the past few decades to eradicate the virus through vaccine and antiviral drugs, but still battle continues. In this review, the possible drug targets for discovery and development of potential antiviral drugs against structural proteins of dengue virus, the current development status of the antiviral drugs against dengue around the world, and challenges that need to be addressed to overcome the shortcomings in the process of drug discovery have been discussed.