Centers for Research on Structural Biology of Infectious Diseases   4

AMENDMENT FOUR

The purpose of Amendment Four is to:

1) Respond to questions received regarding this solicitation.

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AMENDMENT THREE

The purpose of Amendment Three is to:

1) Respond to questions received regarding this solicitation.

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AMENDMENT TWO

The purpose of Amendment Two is to:

1) Respond to questions received regarding this solicitation.

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AMENDMENT ONE

The purpose of Amendment One is to:

1) Provide a cut-off date for submission of questions;

2) Respond to questions received regarding this solicitation.

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Introduction

The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), of the Department of Health and Human Services (DHHS) supports research related to the basic understanding of microbiology and immunology leading to the development of vaccines, therapeutics, and medical diagnostics for the prevention, treatment, and diagnosis of infectious and immune-mediated diseases. The NIAID Division of Microbiology and Infectious Diseases (DMID) supports a comprehensive extramural research program focused on the prevention and control of diseases caused by virtually all infectious agents (with the exception of the Human Immunodeficiency Virus). The NIAID is re-competing the Structural Genomics Centers for Infectious Diseases (SGCID) program, herein now referred to as the Centers for Research on Structural Biology of Infectious Diseases (CRSTAL-ID).

In 2007, NIAID established two five-year contracts to support the SGCID program that focused on determining three-dimensional (3D) structures of protein targets of biomedical interest. The SGCID program was re-competed in 2012 and two five-year contracts were awarded to the incumbents. The SGCID program was re-competed again in 2017 and two five-year contracts were awarded to the incumbents:

https://www.niaid.nih.gov/research/structural-genomics-centers-infectious-diseases-resources

1. Seattle Biomedical Research Institute (novated to Seattle Children's Research Institute) (Contract No. HHSN272201700059C)
2. Northwestern University (Contract No. HHSN272201700060C)

To date, the SGCID centers have determined more than 2,700 3D protein structures across bacterial, viral, and eukaryotic pathogens that address NIAID scientific priorities from antimicrobial resistance to emerging infectious diseases, influenza, malaria, and tuberculosis. The solved protein structures provide new insights into protein domains and ascribe new functions to both uncharacterized and previously characterized proteins. Both SGCID centers use small molecule/ligand screening to increase crystallization success rates and to gain functional insight from these protein-ligand interactions. The SGCID centers are now solving structures using high resolution applications of Cryo Electron Microscopy (cryo-EM) technology to include structural vaccinology , and assessment of antibodies structure to inform therapeutics which have been applied to SARS-CoV-2, Respiratory Syncytial Virus, Hepatitis C, Chikungunya, and Enterovirus-D68 and other viruses with pandemic potential.

Importantly, and in alignment with the NIAID dual mandate, the SGCIDs maintain a robust and efficient structure determination pipeline and serve as a structural biology resource poised to respond swiftly to emerging infectious disease threats. The program has been a vital resource and frequently utilized by the infectious diseases research community during the ongoing SARS-CoV-2 pandemic. These efforts have helped inform vaccine, therapeutic, and diagnostic research efforts.

The 3D structure data, expression clones, and peptides for thousands of targets are made freely available. The SGCIDs have distributed over 16,000 expression clones and almost 8,000 purified proteins to the scientific community. Importantly, these SGCID centers provide a 3D structure determination service, with over 1,200 solved 3D structures in response to community requests. Successful projects include collaborations with researchers that leverage the 3D protein structures to elucidate protein function, mechanistically define ligand-binding activities identified during screens and optimal immunogen design. Taken together, the SGCID program has provided structural biology resources for investigators focused on basic research, and towards the development of therapeutics and vaccines for infectious diseases. Their work has resulted in almost 400 publications.

Description

The goal of the CRSTAL-ID program is to continue to support experimental determination of 3D protein structures and other molecules with important biological roles across human pathogens, and pathogen and host proteins involved in host-pathogen interactions. Pathogens include those on the NIAID Category A-C Priority Pathogen lists and organisms associated with emerging and re-emerging infectious diseases:

https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens.

This CRSTAL-ID program will support research projects that utilize experimental approaches to define the molecular mechanisms of protein targets and gain further insight into the functional roles of these targets. Knowledge from these protein structures and their molecular functions will inform: 1) a structural view of biological processes and pathways which will assist systems-level investigations; and 2) insights into functional mechanisms of the protein target(s), either in complex with other biological molecules or with synthetic compounds. Moreover, the CRSTAL-ID will support projects that perform structure-guided vaccine design and drug discovery and will conduct evaluation and validation assays required for therapeutic use against infectious diseases. This rational structure-guided approach will improve selectivity, specificity and optimization of drug and vaccine development pipelines. Of critical importance, the CRSTAL-ID program will support projects on antimicrobial resistance and pandemic preparedness for emerging infectious disease threats with a focus on viruses with epidemic or pandemic potential to aid in coordination of NIAID response efforts. The 3D structure information, reagents and services provided by the CRSTAL-ID centers will be made freely available to the broad scientific community.

The purpose of this solicitation is to provide scientific support to the CRSTAL-ID program through a) generation of 3D structures for targets derived from bacterial, viral, eukaryotic and other human pathogens using state-of-the-art high-throughput (HTP) technologies and structural biology methodologies including x-ray crystallography, nuclear magnetic resonance (NMR), cryo-EM, and structural modeling; b) characterization of molecular functions and biochemical properties of selected targets; c) evaluation of structure-guided design and functional studies of drug targets and vaccine candidates; d) provision of pandemic preparedness and rapid response to emerging infectious diseases threats and programmatic priorities; e) provision of a 3D structure determination service to the external scientific community; and f) dissemination of contract generated resources, including all 3D structure information and reagents.