NCI Program for Natural Products Discovery - Cures

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Accomplishments: Aim 1. Create new technologies to build an enhanced NP pre-fractionated library amenable to modern high-throughput targeted screening programs. -New high-throughput natural products chemistry infrastructure has been built, outfitted and implemented on the NCI at Frederick campus on Ft. Detrick. Implemented technologies enable the production of up to 175,000 fractionated natural product samples per year as well as the automated storing and sorting of up to 1,100,000 fractions and the plating (in 384-well plates) of 5,000,000 test samples per year. -The NPNPD has helped create new robotic systems, enhanced lyophilization capabilities, automated purification and analytical chemistry systems, liquid handling systems and integrated robotic interfaces between these automated systems. -The NPNPD has written code for new automation programs for the creation, annotation, storage, plating drying, and purification of natural product samples. -These technologies and programs have already been successfully transferred to additional research institutes (Univ. Michigan, Univ. Mississippi, and the University of Pretoria, S. Africa). Aim 2. Expand the chemical diversity available to the public from culturable microorganisms with new methods and libraries. -The NPNPD has built, outfitted and implemented new facilities and methods for the high-throughput cultivation and extraction of microorganisms at the NCI at Frederick campus on Ft. Detrick. -The NPNPD has created, through a contract with the University of Oklahoma Citizen Science Program a library of 13,000 individual soil fungi collected throughout the United States. The NPNPD has processed, photographed, cultured and determined the ITS sequence and taxonomy of all of these samples. -The NPNPD has so far cryo-vialed 100,000 individual culture vials of fungi accessioned by the NCI for preservation and distribution of this resource. -The NPNPD has completed acquisition of 6700 Australian marine microbes from the Australian Institute of Marine Science. -Initial liquid cultivation, extraction and prefractionation protocols for fungi have been reduced to practice. Aim 3. Provide the pre-fractionated library to screening centers worldwide to accelerate drug discovery. -The NPNPD has so far produced 450,000 pre-fractionated extracts and plated 18,000,000 wells on 28,000 384-well plates for distribution. -The NPNPD has made available to the public 326,000 individual pre-fractionated natural product samples in 384-well plates. -The NPNPD shipped 4,500,000 screening samples so far (more than the combined shipments of NCI natural product samples throughout the previous 40 year history of the NCI Natural Products Repository). -The NPNPD has so far received and processed 60 requests for material transfer agreements (MTAs) from research organization around the world to enable these centers to screen NPNPD pre-fractionated natural product samples. -The NPNPD has so far completed 30 individual MTAs with research institutions worldwide (see Appendix section for a detailed list). -The NPNPD published a manuscript on this specific aim in ACS Chemical Biology in 2018, it was the cover article. Aim 4. Provide high throughput screening support for researchers to enable targeted discovery efforts. -The NPNPD has entered into joint research agreements with NIAID, NCATS, NCCIH, the Department of Defense, and Astra Zeneca UK to pursue joint drug discovery efforts using NPNPD pre-fractionated libraries. -The NPNPD has successfully supported multiple screens for researchers at the CCR, Univ. of Texas, Univ. of Iowa, Vanderbilt Univ., Baylor College of Medicine, Yale Medical School, Walter Reed Army Institute of Research, NIAID, and Astra Zeneca. -The NPNPD is a participant in a funded international research program let by University of Pretoria (S. Africa) which will use NPNPD technologies to develop a library of fractions of African origin to be screened in Africa, Australia, India, Europe, the United Kingdom and the NCI. -The NPNPD published a manuscript on this specific aim in Natural Product Reports in 2020, it was the cover article. Aim 5. Provide faster analytical resources (isolation, structure elucidation, re-supply) to expedite translational pipelines. -The NPNPD has created, outfitted and implemented high-throughput secondary purification and analytical chemistry capabilities at the NCI at Frederick campus on Ft. Detrick. -The NPNPD has created the capability to perform up to 500 purifications together with plating and drying of 10,000 sub-fraction samples per week. -The NPNPD has successfully utilized this capability on several programs with the CCR/NCI, Astra Zeneca and the Department of Defense. -The NPNPD produced and shipped 25,000 purified subfractions derived from active NPNPD fractions to screening centers. -The NCI has transferred these technologies to the University of Mississippi and University of Pretoria, S. Africa, and Sweden. -The NPNPD published a manuscript on this specific aim in ACS Chemical Biology in 2020, it was the cover article. Aim 6. Establish a public database and bioinformatics platform to broaden input and expand impact. -The NPNPD is in the process of modernizing legacy natural product databases to bring them into more modern and easily compatible database structures. These databases include information on taxonomy, amount, collection location information, photographs of source organisms, voucher collections at the Smithsonian Institution, shipping records, bioassay results, analytical chemistry files (including chemical structures, NMR, IR and MS files) etc. -The NPNPD has reached agreement with the Smithsonian Institution and NIH to include the NCI Natural Product Voucher Collection as an Institutionally Significant Scientific Collection to be protected in perpetuity. This agreement includes aspects of public access to voucher specimens. -The NPNPD has developed Self-Organizing Map (SOM) bioinformatic systems for the rapid prioritization of natural products chemistry efforts based on analysis of their biological activity. -The NPNPD published a manuscript on this specific aim in Molecular Oncology in 2021, it was the cover article.