R01AI158569

Advancing the Development of a Novel Class of Small Molecules for Treating Pan-Coronavirus Infections - Abstract

For the past decade, our laboratory has been studying the role of cellular kinases in intracellular trafficking of RNA viruses and as targets for broad-spectrum antivirals. Furthermore, we have provided a proof of concept for the potential feasibility of the host-targeted broad-spectrum antiviral approach by demonstrating that the inhibition of two cellular kinases, AAK1 and GAK, by novel or the approved anticancer drugs, sunitinib and erlotinib, protects mice from dengue and Ebola viruses with a high barrier to resistance.

Since the therapeutic index (TI) of this drug combination is narrower for SARS-CoV-2 infection, here, we focus on an independent class of compounds, the isothiazolo[4,3-b]pyridine-based RMC-113 series, that emerged from our prior work, but does not inhibit AAK1 or GAK. We showed that RMC-113 and 25 related analogs have potent broad-spectrum antiviral activity with a high barrier to resistance. Excitingly, RMC-113 reduces SARS-CoV-2 titer to undetectable levels at non-toxic concentrations and binds PIKFYVE, a cell kinase that regulates endosomal trafficking. We hypothesize that RMC-113 analogs inhibit both multiple distinct steps in the SARS-CoV-2 life cycle and the inflammatory response to this virus, in part by targeting PIKFYVE, thereby offering attractive and safe candidate inhibitors to combat SARS-CoV-2, other pandemic coronaviruses, and other emerging viruses.

In Aim 1, we will use a multi-dimensional medicinal chemistry approach to optimize the TI and PK profile of lead RMC-113 analogs and define their in vitro therapeutic potential as broad anticoronavirus inhibitors. Aim 2 will determine the effect of prioritized analogs and apilimod, a repurposed drug candidate for COVID-19 that inhibits PIKFYVE, on viral replication, cytokine response, and tissue injury in organoids derived from excised normal lung tissue supplemented with PBMCs from 20 human donors and in two rodent models. Aim 3 will generate ADME-toxicity and safety pharmacology datasets to select pre-IND candidates. In Aim 4, we will probe the mechanism of antiviral action of RMC-113. We will validate PIKFYVE as a candidate target and use an unbiased CRISPRi screen to identify RMC-113's target(s) and profile its chemical-genetic landscape. In parallel, we will design a clickable RMC-113 probe to confirm the molecular target via activity-based protein profiling and to monitor target engagement. Lastly, we will probe functional relevance and specific roles of PIKFYVE and other candidates emerging via these approaches in SARS-CoV-2 infection and validate them as the molecular target(s) mediating the antiviral effect.

The predicted immediate impact is that this project will provide insight into the therapeutic potential and MOA of apilimod, a repurposed drug candidate (beyond the reported effect on viral entry), and will establish a unique human lung organoid model for studying SARS-CoV-2 pathogenesis and response to treatment under more natural conditions. In the longer term, successful completion of our study will deliver a drug-like small molecule candidate designed to protect against the resurge of COVID-19 and to provide readiness for future outbreaks with coronaviruses and other emerging viruses.

The Leland Stanford Junior University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

Emergency Awards: Rapid Investigation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) (R01 Clinical Trial Not Allowed) (PAR-20-178)

COVID-19 $1,435,812 (41%) percent of this Project Grant was funded by COVID-19 emergency acts including the American Rescue Plan Act of 2021 and the 2020 Coronavirus Preparedness and Response Supplemental Appropriations Act.
Amendment Since initial award the total obligations have increased 351% from $779,425 to $3,512,637.