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Principal Investigator: Ian Bass Seiple
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $84,553
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
This proposal summarizes ongoing projects in our laboratory focused on natural product classes that
have promising biological activity but are burdened with limitations that have prevented them from reaching their
therapeutic potential. These classes are structurally complex and modification of their is challenging by
semisynthetic and biosynthetic methods. We aim to develop fully synthetic routes to these classes from simple
building blocks, enabling chemical modification to overcome their limitations. These efforts are informed by
binding data (X-ray or cryo-EM) for each class. The primary goals of project outlined herein are to 1) expand
structure–function relationships for each of these important classes of molecules, and 2) discover potent analogs
that are suitable for hit-to-lead optimization or for use as tools to study biological systems. Additionally,
development of the synthetic routes themselves is highly innovative, and is often accompanied by development
of methods that are broadly applicable in chemistry. These efforts mirror our work on streptogramin and
lankacidin antibiotics, which was a primary focus in our Early Stage Investigator MIRA (R35GM128656), and led
to structural reassignments and to a potent hit compound with activity against resistant strains in vivo.
Much of the biology for this work will be enabled by collaboration. Five of the projects summarized herein
focus on the development of novel antibiotics that target the ribosome and membrane proteins. Due to our
ongoing work in this area, we have several collaborations in place to evaluate the antimicrobial activity, in vivo
efficacy, and target engagement of new analogs. Beyond antibiotics, we propose to synthesize and derivatize
classes that target Hsp90, an anticancer target, and eEF1A, an anticancer and antiviral target. Evaluation of
these compounds for inhibitory activity, isoform selectivity, and binding will be enabled by new collaborations,
expanding the scope of our research. With chemical innovation paired with strong biological investigation, we
anticipate that the work outlined herein will lead to exciting discoveries in chemical synthesis and to the discovery
of hit compounds for the treatment of bacterial infections, cancer, and SARS-CoV-2.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Area><Bacterial Infections><Binding><Biological><Biology><COVID-19 virus><COVID19 virus><Cancers><Chemicals><Chemistry><CoV-2><CoV2><Collaborations><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Derivation><Derivation procedure><Development><Electron Cryomicroscopy><Evaluation><Goals><Investigation><Investigators><Isoforms><Laboratories><Malignant Neoplasms><Malignant Tumor><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methodology><Methods><Miscellaneous Antibiotic><Modification><Molecular Interaction><Natural Products><Property><Protein Isoforms><Research><Research Personnel><Researchers><Ribosomal Proteins><Roentgen Rays><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Streptogramins><Structure-Activity Relationship><Surface Proteins><Therapeutic><Viral><Work><Wuhan coronavirus><X-Radiation><X-Ray Radiation><X-ray><Xray><analog><anti-cancer><anti-microbial><antimicrobial><bacteria infection><bacterial disease><biologic><biological systems><chemical structure function><chemical synthesis><coronavirus disease 2019 virus><coronavirus disease-19 virus><cryo-EM><cryoEM><cryogenic electron microscopy><developmental><hCoV19><in vivo><innovate><innovation><innovative><lead optimization><malignancy><method development><nCoV2><naturally occurring product><neoplasm/cancer><novel><prevent><preventing><resistance strain><resistant strain><scaffold><scaffolding><structure function relationship><tool>