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.
No atomic resolution model is available for any SRD5A, a prerequisite to understand the physiology of these enzymes at a molecular level and for the rational, structure-guided design of selective inhibitors for prevention and therapy of prostate cancer, the second-leading cause of cancer-related deaths in the western world.
The project will allow training of Sapienza young researchers in membrane protein biochemistry and single-particle cryo-electron microscopy (cryo-EM), absent in Sapienza and only at the initial stages in Italy, in the Institution where the Nobel Prize for this methodology was awarded in 2017
The expected results are:
1. Structure of one or more members of the steroid reductase family (SRD5A). This information is critical for the rational design of isoform-specific inhibitors for therapy of prostatic hyperplasia, hormone deprivation refractory prostatic cancer and male pattern baldness.
2. Training of young Italian scientists in single particle cryo-electron microscopy, a revolutionary technique that allows macromolecule structure determination in solution-like conditions (Nobel Prize for Chemistry, 2017).
3. Training and expertise in membrane proteins crystallization, purification and reconstitution in lipid-filled scaffolds (nanodiscs and liposomes).
4. Production of new inhibitors of SRD5A enzymes, to be used as drug leads in collaboration with the Dept of Drug Technology of Sapienza University, with great interests in intellectual property development in pharmacology.
The present market for finasteride, currently marketed by Merck, to inhibit SRD5A1 and SRD5a2 enzymes is 500 million dollars, in the USA alone. The development of inhibitors with better selectivity (i.e. SRDA5A only) and potency has a huge commercial potential and heavily relies on the determination of the structure of members the SRD5A family, the main goal of this project.