About

William Gerwick, Ph.D., is a Distinguished Professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego. His research focuses on exploring the unique natural products of marine algae and cyanobacteria for biomedical applications. His group has been involved in discovering and evaluating these organisms' highly unusual metabolites for their potential in cancer, inflammation, infectious diseases including tropical diseases such as malaria, Chagas’ disease, and leishmaniasis, as well as neurochemical pathways, antiviral activity against SARS-CoV-2, and agricultural uses. Dr. Gerwick's team uses SCUBA to collect marine samples worldwide and grows many of these organisms in the laboratory, testing extracts for bioactivity, and isolating active compounds using NMR and MS. They have developed new methods of structure analysis, such as the Deep Learning-based SMART technology, and collaborate with academic and industrial partners to develop lead molecules through synthetic chemistry and molecular modeling, especially targeting parasitic diseases.

Research topics

• Biology
• Chemistry
• Computational biology
• Artificial Intelligence
• Genetics
• Computer Science
• Bioinformatics
• Biochemistry
• Chromatography
• Biological system
• Remote sensing
• Cell biology
• Ecology
• Virology
• Geography

Selected publications

• Identification of Hoiamide A as an Inducer of Oxidative and Endoplasmic Reticulum Secretory Pathway Stress

  Journal of Natural Products · 2026-05-04

  articleOpen access

  The endoplasmic reticulum (ER) to Golgi secretory compartment of eukaryotic cells is highly sensitive to changes in intracellular homeostasis. Using a primary screening assay that monitors the function of this pathway, we prioritized a cyanobacterial extract from the Red Sea that decreased secretion of a bioluminescent reporter, Gaussia luciferase (GLuc), in living cells. A comparison of LCMS2 data against the GNPS database revealed a match for macrocyclic depsipeptide hoiamide A (1). Biological testing confirmed the ability of 1 to induce a mixed, non-lethal stress response in human U87-MG glioblastoma cells; analysis of stress markers by qRT-PCR revealed early upregulation of superoxide dismutase 1 (SOD1) and C/EBP-homologous protein (CHOP) relative to the control. Co-treatment of cells with 1 (100 nM to 3 μM) and antioxidant N-acetylcysteine afforded full protection from 1-induced decreases in GLuc secretion. We report that terminally differentiated human SH-SY5Y neuroblastoma cells, with a neuron-like phenotype, are highly sensitive to nanomolar concentrations of 1, whereas undifferentiated cells remained viable at 3 μM. These results expand the known biology of hoiamides and suggest that neurotoxic potential of 1 is likely due to an inherent failure of neurons to adapt to the loss of redox homeostasis and sustained ER stress.

  PublisherDOI

• Structure of a putative terminal amidation domain in natural product biosynthesis

  Structure · 2025-03-13 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Osmolyte chemical diversity in Lingulaulax polyedra red tides: a critical overlooked factor to respiratory irritations?

  Harmful Algae · 2025-11-08

  articleOpen access

  • Environmental extracts containing yessotoxin do not induce inflammation in macrophage raw cells • Unprecedented levels of sulfur osmolytes, including DMSP, were detected • Unusual nitrogenous osmolytes enrichment over the course of the bloom was observed The detrimental effects on human health sometimes observed during blooms of Lingulaulax polyedra have been formerly attributed to the yessotoxin analogs this species produces. In this paper we show that natural concentrations of yessotoxin analogs present in seawater and sea spray aerosols during an unprecedented L. polyedra bloom in 2020 in Southern California did not induce inflammation in mammal macrophage cells, questioning the role played by yessotoxin in causing respiratory irritations. This bloom was associated with unprecedented levels of particulate dimethylsulfoniopropionate (2.74 ± 1.63 to 10.11 ± 1.39 µM), gonyol and several new structural analogs ofgonyol . We profiled the metabolic content of dinoflagellate cells and recorded increasing amounts of quaternary amines of the betaine family (carnitine, actinin, ectoine) as the bloom progressed. Being precursors of sulfur and nitrogenous small volatile compounds, we hypothesize that, in addition to their recognized role in climate processes, these sulfur and nitrogenous osmolytes may also play a key role in health-related issues reported during intense L. polyedra blooms.

  PublisherDOI

• Author Correction: A universal language for finding mass spectrometry data patterns

  Nature Methods · 2025-08-08

  erratumOpen access
  PublisherOA PDFDOI

• Isolation and Biosynthesis of Hyellamide, a Glycosylated N-Acyltyrosine Derivative, from the Cyanobacterium <i>Hyella patelloides</i> LEGE 07179

  Journal of Natural Products · 2025-02-26

  articleOpen access

  Recent analyses of genome data indicate that members of the cyanobacterial order Pleurocapsales show tremendous potential for natural product discovery. However, only a few compounds have been reported from this order. Here, we report the isolation of hyellamide (1), a glycosylated N-acyl tyrosine-derived eneamide, from the pleurocapsalean cyanobacterium Hyella patelloides LEGE 07179. The putative biosynthetic gene cluster for 1 was identified in the genome of the producing organism and a biosynthetic proposal is presented. This work sheds light on the chemistry of the Pleurocapsales and expands the chemical repertoire of cyanobacterial natural products to include N-acyl tyrosine-derived molecules.

  PublisherOA PDFDOI

• A universal language for finding mass spectrometry data patterns

  Nature Methods · 2025-05-12 · 44 citations

  articleOpen access

  Despite being information rich, the vast majority of untargeted mass spectrometry data are underutilized; most analytes are not used for downstream interpretation or reanalysis after publication. The inability to dive into these rich raw mass spectrometry datasets is due to the limited flexibility and scalability of existing software tools. Here we introduce a new language, the Mass Spectrometry Query Language (MassQL), and an accompanying software ecosystem that addresses these issues by enabling the community to directly query mass spectrometry data with an expressive set of user-defined mass spectrometry patterns. Illustrated by real-world examples, MassQL provides a data-driven definition of chemical diversity by enabling the reanalysis of all public untargeted metabolomics data, empowering scientists across many disciplines to make new discoveries. MassQL has been widely implemented in multiple open-source and commercial mass spectrometry analysis tools, which enhances the ability, interoperability and reproducibility of mining of mass spectrometry data for the research community.

  PublisherDOI

• Environmentally controlled production of pagoamide A in marine macroalgae by an intracellular bacterial symbiont

  Current Biology · 2025-12-16

  article
  PublisherDOI

• Cyanobacteria Join the Kahalalide Conversation: Genome and Metabolite Evidence for Structurally Related Peptides

  Journal of the American Chemical Society · 2025-08-19 · 4 citations

  articleOpen accessSenior authorCorresponding

  Kahalalide F is a cyclic depsipeptide with notable anticancer properties, initially discovered from the green alga Bryopsis sp. and its molluscan predator Elysia rufescens. Recent studies have pinpointed a bacterial endosymbiont of the green alga, Candidatus Endobryopsis kahalalidefaciens, as the true producer of kahalalide F. In the present work, we characterize a closely related kahalalide F analog, kahalalide Z5, from the marine cyanobacterium Limnoraphis sp. collected in the Las Perlas Islands, Panama, and propose the structures of several related compounds by detailed MS analysis. To uncover novel metabolites and prioritize them for targeted isolation from this organism, we employed a robust metabolomics strategy combining LC-MS/MS with SMART NMR and DeepSAT, artificial intelligence platforms trained to infer chemical structures from 1H–13C HSQC NMR data. This integrated approach annotated a compound with structural similarities to kahalalide F, which we subsequently characterized using a suite of spectroscopic techniques and chemical degradation studies. Whole-genome sequencing of the producing strain further revealed a NRPS biosynthetic gene cluster that aligns with the structural features of kahalalide Z5. This study identifies the marine cyanobacterium Limnoraphis sp. as an independent source of kahalalide F-like molecules. This work broadens the phylogenetic spectrum of organisms capable of producing these bioactive compounds, reveals marine cyanobacteria as producers of an increased repertoire of unique natural products, and illustrates the potential of AI-enhanced metabolomic and genomic analyses to streamline the discovery and characterization of complex biomedically relevant natural products.

  PublisherOA PDFDOI

• Green genes from blue greens: challenges and solutions to unlocking the potential of cyanobacteria in drug discovery

  Natural Product Reports · 2025-07-15 · 5 citations

  reviewOpen access

  Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges.

  PublisherDOI

• Controlling Megasynthetase Module–Module Interactions through β-Hairpin Docking Domain Engineering

  ACS Chemical Biology · 2025-11-25

  articleOpen access

  Bacteria manufacture a diversity of natural products with pharmaceutical value, many from modular polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS), or hybrid pathways. In these pathways, each module extends a biosynthetic intermediate by an acyl unit (PKS) or amino acid (NRPS), employing a carrier domain (CP) to deliver the pathway intermediate to successive active sites and to the subsequent module. Docking domains (DD) at polypeptide termini ensure pathway fidelity by specific noncovalent association of sequential modules. The vatiamide biosynthetic gene cluster encodes a rare trifurcated pathway, enabled by a short linear motif (SLiM) at the C-terminus of VatM that docks with identical β-hairpin domains (βHDs) at the N-termini of VatN, VatQ, and VatS. Taking inspiration from Nature, we examined the utility of DDs for engineering by quantitating affinity and catalytic throughput in the Vat system and an unrelated SLiM-βHD dock from the carmabin pathway. The SLiM-βHD dock was the sole determinant of affinity of natural and engineered module partners (Kd ∼ 1 μM). The effectiveness of engineered DDs was evaluated relative to natural partners and docks. DD affinity was predictive of catalytic success in most, but not all, of the dozen cases tested. Thus, while the DD determines affinity and selectivity, other factors also affect catalytic throughput when a DD is engineered into a non-native environment. This study enhances our understanding of the interactions that enforce PKS/NRPS pathway fidelity and highlights the challenges of engineering these systems to diversify the repertoire of natural products.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R23CA042850

  NIH · $141k · 1990

• NIH Grant U01TW006634

  NIH · $7.8M · 2015

• Unified Computation Tools for Natural Products research

  NIH · $547k · 2013–2025

• NIH Grant R21AI127505

  NIH · $421k · 2019

• NIH Grant R01GM118815

  NIH · $1.2M · 2021

Frequent coauthors

• Lena Gerwick

  Scripps Institution of Oceanography

  285 shared

• Pieter C. Dorrestein

  University of California, San Diego

  247 shared

• Evgenia Glukhov

  Scripps Institution of Oceanography

  187 shared

• Kerry L. McPhail

  Oregon State University

  167 shared

• Jehad Almaliti

  University of California, San Diego

  160 shared

• Niclas Engene

  Florida International University

  148 shared

• Albán R. Pereira

  143 shared

• Thomas F. Murray

  126 shared

Awards & honors

• Fellow, American Society of Pharmacognosy (2008)
• UC San Diego Chancellor's Associates Faculty Excellence Awar…
• American Society of Pharmacognosy Norman Farnsworth Research…
• Fellow of the American Association for the Advancement of Sc…
• Paul Scheuer Award, Gordon Conference on Marine Natural Prod…