SBIR-STTR Award

A microED pipeline for the pharmaceutical and biotechnology industry
Award last edited on: 5/20/2023

Sponsored Program
SBIR
Awarding Agency
NIH : NIGMS
Total Award Amount
$1,402,767
Award Phase
2
Solicitation Topic Code
859
Principal Investigator
Giovanna Scapin

Company Information

NanoImaging Services Inc

4940 Carroll Canyon Road Suite 115
San Diego, CA 92121
Location: Single
Congr. District: 52
County: San Diego

Phase I

Contract Number: N/A
Start Date: 6/1/2021    Completed: 5/31/2023
Phase I year
2021
Phase I Amount
$1
Direct to Phase II

Phase II

Contract Number: 1R44GM140666-01
Start Date: 6/1/2021    Completed: 5/31/2023
Phase II year
2021
(last award dollars: 2022)
Phase II Amount
$1,402,766

Microcrystal electron diffraction (microED) is an emerging structure determination technique of high interest tothe pharmaceutical and biotechnology industries. MicroED can rapidly determine atomic-resolution structuresfrom microcrystals with minimal sample requirements. The goal of this Phase II proposal is to develop and deliverrobust service offerings for microED structure determination to the commercial sector. Improvements to criticalsteps in this workflow will enable analysis for any suitable sample type while offering a level of efficiency thatmeets the requirements of Structure-Based Drug Design (SBDD) and medicinal chemistry programs. Thepermissive sample requirements, minimal time requirements, and high-quality structures generated makemicroED an attractive structure determination technique with broad applications for small molecules, peptides,natural products, proteins and protein-drug complexes. An efficient microED pipeline will help to reduce the costof drug development and reduce the time it takes a drug to make it into the clinic.MicroED uses a transmission electron microscope (TEM) to collect diffraction data from small crystallinesamples. The steps required include transferring crystalline samples to TEM grids; collecting a series ofcontinuous-rotation, electron-diffraction datasets from single crystals; processing the diffraction data and refiningthe atomic model. An initial development phase demonstrated collection of excellent quality diffraction datasetsfor more than 20 samples, and the ability to deliver atomic resolution maps suitable for addressing the needs ofour pharmaceutical clients who took part in alpha and beta testing. New methods will be developed, and existingapproaches optimized to improve every step of this pipeline, substantially increase throughput, and improve finalmaps and models. Specific aims include: (1) Optimizing TEM grid preparation to ensure the transfer of a sufficientnumber of high-quality target microcrystals onto the grid substrate without damaging them or altering theirproperties. (2) Developing an automated, high-throughput data collection system capable of unattended,overnight data acquisition for multiple different samples, and of providing information to inform data scaling anddetermining handedness of chiral small molecules. (3) Automating and improving data processing, phasing andmodel refinement including real-time data reduction, brute force on-the-fly phasing, and investigating a widerange of new programs and methods.In parallel with the Phase II research plan, a full commercial service offering spanning the complete range ofmicroED capabilities will be developed.

Public Health Relevance Statement:
Narrative High-resolution structures of proteins, small molecules and their complexes are a critical part of the drug discovery process collectively known as Structure-Based Drug Design (SBDD) in the pharmaceutical and biotechnology industries. MicroED is an emerging structural technique that will support advancement of human health through enabling novel molecular targets for chemotherapies and new biologics. NanoImaging Services (NIS) proposes to build upon an initial microED service offering to deliver an expanded suite of services aligned with the unique needs of the industrial market, addressing reproducibility, throughput, affordability, speed, and flexibility.

Project Terms:
Acetaminophen ; APAP ; Acetamidophenol ; Acetominophen ; Hydroxyacetanilide ; Paracetamol ; Algorithms ; Automation ; Biotechnology ; Biotech ; Biotin ; Vitamin H ; coenzyme R ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Client ; Commercial Sectors ; Crystallization ; Data Collection ; Drug Design ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Feedback ; Goals ; Health ; Human ; Modern Man ; Industrialization ; Industry ; Handedness ; Laterality ; Maps ; Methods ; Online Systems ; On-Line Systems ; online computer ; web based ; Peptides ; Progesterone ; Corpus Luteum Hormone ; Delta4-pregnene-3,20-dione ; Pregn-4-ene-3,20-dione ; Pregnenedione ; Therapeutic Progesterone ; Proteins ; Research ; Rotation ; Computer software ; Software ; Specificity ; statistics ; Testing ; Time ; Work ; Drug Costs ; Data Set ; Dataset ; base ; Microscope ; Electron Microscope ; improved ; Procedures ; Phase ; Biological ; Series ; X-Ray Crystallography ; Single Crystal Diffraction ; X Ray Crystallographies ; X-Ray Diffraction Crystallography ; X-Ray/Neutron Crystallography ; Xray Crystallography ; Ensure ; data quality ; Robot ; Research Specimen ; Specimen ; Knowledge ; programs ; Hour ; Complex ; Event ; Clinic ; Techniques ; System ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; interest ; Services ; chiral molecule ; Speed ; Structure ; novel ; Modeling ; Sampling ; Property ; drug development ; drug discovery ; data processing ; computerized data processing ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; small molecule ; Address ; Data ; Molecular Target ; Reproducibility ; Resolution ; Collection ; transmission process ; Transmission ; Preparation ; Molecular ; Process ; Development ; developmental ; Image ; imaging ; nanoimaging ; nano imaging ; cost ; novel strategies ; new approaches ; novel approaches ; novel strategy ; three dimensional structure ; 3-D structure ; 3-dimensional structure ; 3D structure ; data acquisition ; chemotherapy ; flexibility ; flexible ; data reduction ; screening ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; electron diffraction ; crystallinity ; Natural Products ; improved outcome ; microscopic imaging ; microscope imaging ; microscopy imaging ; Structural Protein ; Micro Electron Diffraction ; MicroEd ; data analysis pipeline ; data processing pipeline ;