Virology

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Large-scale, systems-based analyses drive our discovery of host factors that control viral replication Mechanism of action studies involve CRISPR/Perturb-Seq, chemoproteomics, and super-resolution microscopy as well as standard molecular and cellular biology. In this way, we have identified and characterized host and innate immune adaptors that control replication of influenza, WNV, DENV, SARS-CoV2, HIV-1, and other viruses. Elucidation of these critical circuits that control disease provide critical insights into viral pathogenesis and outcomes of infection. They also represent potential therapeutic targets for the development of next-generation antiviral therapies.

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These projects were led by Dr. Nacho Mena (Scripps).

 

HIV Cure

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The development of a curative strategy is a critical component of eradicating HIV/AIDS. The Chanda Lab identified a novel and promising class of latency reversal agents (LRAs) that can potentially reactivate HIV-1 without inducing a widespread immune response. We are optimizing current leads while seeking new, synergistic LRAs. Our goal is to produce one or more fully optimized molecules, suitable for preclinical IND enabling studies. Patients with HIV/AIDS would be cured by a combination of LRAs and immune regulators. These efforts are funded by Reversing Immune Dysfunction for HIV-1 (RID-HIV), a Martin Delaney Collaboratory for HIV Cure Research. This flagship NIH program fosters dynamic, multidisciplinary collaborations between basic, applied, and clinical researchers studying HIV persistence and developing potential curative strategies.

 

This project is in collaboration with Dr. Lars Pache (SBP).

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Innate Immunity

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The initiation and progression of innate immune responses in various cell types is driven by pathogen or damage-associated molecular patterns. Our aim is to uncover the underlying mechanisms of innate pathway activation in viral infection and inflammatory disorders. We have previously described utilizing genome-level technologies to identify and mechanistically characterize novel factors that regulate innate immune pathways triggered by viruses, including cGAS, RIG-I, and TLR7/9. Factors that represent viable therapeutic targets are pursued through our drug discovery and chemoproteomics platforms to develop new antivirals, vaccine and immunotherapy adjuvants as well as treatments for autoimmune diseases.

 

This project is led by Dr. Sunnie Yoh (Scripps).

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Drug Discovery

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Our program is geared towards pandemic-preparedness through prevention and treatment. We are focused on discovering safe and orally bioavailable antivirals against major human pathogens that can cause epidemics or pandemics, including influenza, coronaviruses and flaviviruses. With support from the Department of Defense, we are also finding broad-spectrum inhibitors of respiratory viruses, while the Gates Foundation funds our efforts to create antivirals for "undruggable" influenza and coronavirus proteins. Additionally, we are searching for small molecules that have immune-stimulatory properties for use as vaccine adjuvants or in conjunction with novel cancer immunotherapies. To achieve this, we have deployed novel assays and high-throughput technologies to identify lead compounds. All small molecule-protein interactions are interrogated by our chemoproteomics pipeline that expands the druggable space by highlighting previously undiscovered binding sites. These efforts are taking place at Calibr, which has established an unparalleled track record in the nonprofit world of advancing innovative drug programs from discovery through Phase 2 clinical studies.

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This project is led by Dr. Naoko Matsunaga (Calibr).

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Neurodigenerative Disease

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We are exploring uncharted territory by investigating the role of innate immunity in neurodegenerative diseases, including Parkinson's, Huntington's, and Alzheimer's. Our aim is to uncover the underlying mechanisms of aberrant cGAS/STING pathway activation in microglia and astrocytes that contribute to chronic inflammatory responses, which lead to neuronal damage.We previously identified PQBP1 as a cellular sensor of retroviral capsids that triggers the cGAS/STING pathway, while others have implicated this factor in sensing of misfolded proteins such as Tau,-synucleinand amyloid- which are associated with neurodegenerative disease. We seek to determine the mechanism of sensing of misfolded proteins by microglia and PQBP1 involvement in the process. These studies will allow us to understand the innate immune system’s ability to distinguish between self and non-self. This new area of research represents an exciting opportunity for the lab to make a significant impact in the field of neurodegeneration.

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This project is led by Dr. Sunnie Yoh (Scripps).

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