Structure and function of the SRD5A family of enzymes that mediate testosterone action.

Anno
2018
Proponente Beatrice Vallone - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Abstract

Our objective for this project is to determine the structure of one or more members of the steroid reductase family of enzymes (SRD5A), to serve (i) as a template for the rational, structure-guided design of new drugs to treat prostate cancer and (ii) for the understanding of their role in steroid physiology, including neuro steroids in the central nervous system (1,2).
This proposal has the potential of providing a seminal contribution furthering our understanding and exploiting the role of steroids and their inhibitors in pharmacological sciences. Steroids are ubiquitously involved in cancer, deeply affect SNC development and influence the severity of neuropsychiatric disorders as well as aggressive, cognitive and sexual behavior. As of today, no atomic resolution model is available for any SRD5A, a prerequisite not only to understand the physiology of these enzymes at a molecular level, but also for the rational design of selective inhibitors to be used in the prevention and therapy of prostate cancer, the second-leading cause of cancer-related deaths in the western world. Indeed, synthetic SRD5A inhibitors include prostate cancer and benign prostatic hyperplasia drugs, such as finasteride and dutasteride. Scarce selectivity for the different SRD5A isoforms and long term inactivation of its enzymatic activity cause severe adverse long-lasting effects that pose limitations to the usage and efficacy of these drugs in oncology and other areas such as therapy of male pattern baldness (MPB), of acne and hormone replacement therapy. Our findings could also pave the way towards a deeper understanding of the mechanism of action of neurosteroids in the SNC and their exploitation in the therapy of mental disorders.
The present project entails a tight collaboration between the Department of Biochemical Sciences at Sapienza University in Rome, and the Department of Physiology and Cellular Biophysics at Columbia University in New York.

ERC
LS1_2, LS1_9, LS7_4
Keywords:
BIOCHIMICA, BIOLOGIA STRUTTURALE E CRISTALLOGRAFIA, SCOPERTA DI FARMACI, MALATTIE RARE, PROTEINE RICOMBINANTI

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