About

Ben Shen, Ph.D., is a Professor in the Department of Chemistry and the Department of Molecular Medicine at the University of Florida. He also serves as the Director of the Natural Products Discovery Center at Scripps Research. Dr. Shen earned his Ph.D. in Organic Chemistry and Biochemistry from Oregon State University in 1991, following a Master of Science degree in Chemistry from The Chinese Academy of Sciences in 1984 and a Bachelor of Science degree in Chemistry from Hangzhou University in 1982. His research focuses on natural products, including the enediyne family, leinamycin family, bacterial diterpenoids, and thiocarboxylic acid-containing or derived natural products. Dr. Shen leverages the Natural Products Discovery Center (NPDC) strain collection for natural product and drug discovery, emphasizing the challenges and opportunities in natural product research and the use of natural products as small molecule probes.

Research topics

• Chemistry
• Biochemistry
• Biology
• Stereochemistry
• Medicine
• Microbiology
• Combinatorial chemistry
• Pharmacology
• Immunology

Selected publications

• Corrigendum to “Bacterial diterpene synthases: New opportunities for mechanistic enzymology and engineered biosynthesis” [Curr Opin Chem Biol, 16 (2012) 132–141

  Current Opinion in Chemical Biology · 2025-03-27

  erratumOpen accessSenior authorCorresponding
  PublisherDOI

• Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research

  HAL (Le Centre pour la Communication Scientifique Directe) · 2025-07-17

  articleOpen access

  Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research'

  PublisherOA PDFDOI

• Chemical Tagging of <i>N</i> -Alkylamine-Containing Natural Products and Pharmaceuticals through C( <i>sp</i> ³ )–H Functionalization

  Journal of the American Chemical Society · 2025-11-14 · 2 citations

  articleOpen access

  -alkylamines. The transformation proceeds under mild, aerobic conditions with blue-light irradiation: flavin analogues mediate sequential α- and β-amino C-H bond scission to generate enamines, which undergo inverse electron-demand Diels-Alder reactions with tetrazine- or nitroalkene-based tagging agents. We assessed biological consequences by cytotoxicity and ligand-binding assays, revealing examples in which tagging either preserves or alters bioactivity. The method's versatility is demonstrated by the efficient synthesis of antibody-drug conjugates derived from the anticancer agent irinotecan.

  PublisherOA PDFDOI

• Discovery of 5-Chlorotryptophan-Containing Antibiotics through Metabologenomics-Assisted High-Throughput Screening

  JACS Au · 2025-11-25

  articleOpen accessSenior authorCorresponding

  Actinomycetota bacteria have specialized in the biosynthesis of antibacterial natural products (NPs), and extract and fraction libraries made from those strains remain a promising source of NP drug leads. Herein, we present a high-throughput screen (HTS), based on engineered Escherichia coli strains expressing the human (Trm5) or bacterial (TrmD) m1G37 tRNA methyltransferase, to discover NPs as novel anti-Gram-negative antibiotic leads. To harness the evolution of NPs with in vivo activity, the cell-based phenotypic HTS was applied to the Actinomycetota extract and fraction library at the Natural Products Discovery Center (NPDC), the Herbert Wertheim UF Scripps Institute for Biomedical Research & Innovation. From a total of 46,031 extracts and 28,739 fractions made from 14,635 strains, extracts from two Actinomycetota species presented reproducible selectivity against the trmD-expressing E. coli strain over the trm5-expressing counterpart. A shared metabolite was identified as 5-chlorotryptophan, which was correlated to the observed selective inhibitory activities. A metabologenomics analysis indicated 5-chlorotryptophan incorporation into two distinct antibiotic nonribosomal peptide families, longicatenamycins and nonopeptins. Notably, the diketopiperazine-containing heptapeptide nonopeptins display rare chemistry, featuring a 5-nitro-tryptophan moiety that has only been described previously as a biosynthetic shunt product. The most active congener of this new family of NPs, nonopeptin D, exhibits a broad-spectrum antibiotic activity, including against selected Gram-negative pathogens.

  PublisherDOI

• Second Generation Tiancimycin-Based Antibody–Drug Conjugates Enabled by Highly Efficient Semi-synthetic Approach Specifically Targeting B-Cell Malignancies

  JACS Au · 2025-07-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  Antibody-drug conjugates (ADCs) are advanced cancer therapeutics that combine an antibody-based delivery system with a cytotoxic payload through chemical linkers. Anthraquinone-fused enediyne (AFE) natural products, such as tiancimycins (TNMs), are emerging payload candidates with exceptional potency and a validated DNA-damaging mechanism of action. In this study, we describe the translation of semisynthetically functionalized TNMs, incorporating various linker chemistries, into ADCs featuring dual variable domain monoclonal immunoglobulin G1 antibodies (DVD IgG1s). DVD IgG1s enable site-specific conjugation and modular antigen-targeting specificity. As a proof-of-principle, keto-TNM A-anti-CD79b DVD IgG1-based ADCs were constructed on the basis of the significance of CD79b as a clinical target, with only one FDA-approved ADC available. Inspired by the structure-activity relationship data, a chemical strategy to synthesize keto-TNM A was developed, which exhibited the highest potency among the TNMs we have examined to date. Keto-TNM A was elaborated to a panel of anti-CD79b DVD IgG1-based ADCs featuring varying linker chemistries. The optimized ADC exhibited potent and selective activity across multiple CD79b-expressing cell lines and, most significantly, patient-derived primary chronic lymphocytic leukemia cells. This study provides an efficient approach to access functionalized AFEs at scale and speed and exploit their utility as payloads for ADCs targeting CD79b and beyond as the next generation immunotherapies.

  PublisherDOI

• The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research

  UNC Libraries · 2025-07-17

  articleOpen access

  Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

  PublisherDOI

• Logical Exploration of Cinnamoyl-Containing Nonribosomal Peptides via Metabologenomic Targeting and Regulator Overexpression

  Journal of the American Chemical Society · 2025-10-07 · 3 citations

  articleOpen access

  ) displayed moderate antiproliferative activity against stomach cancer cells. Our findings highlight a targeted metabologenomic approach combined with transcriptional regulator overexpression as a logical and efficient platform for the discovery of bioactive compounds from nature.

  PublisherOA PDFDOI

• Discovery of 5-Chlorotryptophan-Containing Antibiotics through Metabologenomics-assisted High-throughput Screening

  ChemRxiv · 2025-08-28

  preprintOpen accessSenior author

  Actinomycetota bacteria have specialized in the biosynthesis of antibacterial natural products (NPs), and extract and fraction libraries made from those strains remain a promising source for the discovery of NP drug leads. Herein, we present a high-throughput screen (HTS) based on engineered Escherichia coli strains expressing the human (Trm5) or bacterial (TrmD) m1G37 tRNA methyltransferase to discover NPs as novel anti-Gram-negative antibiotic leads. To harness the evolution of NPs with in vivo activity, a cell-based phenotypic HTS was applied to the Actinomycetota extract and fraction library at the Natural Products Discovery Center (NPDC), the Herbert Wertheim UF Scripps Institute for Biomedical Research &amp; Innovation. From a total of 46,031 extracts and 28,739 fractions made from 14,635 strains, extracts from two Actinomycetota species presented reproducible selectivity against the trmD-expressing E. coli strain over the trm5-expressing counterpart. The shared metabolite was identified as 5-chlorotryptophan, which was correlated to the observed selective inhibitory activities. A genometabolomics analysis indicated 5-chlorotryptophan incorporation into two distinct antibiotic non-ribosomal peptide families, longicatenamycins and nonopeptins. Notably, the diketopiperazine-containing heptapeptide nonopeptins display rare chemistry, featuring a 5-nitro-tryptophan moiety that has only been described previously as a biosynthetic shunt product. The most active congener of this new family of NPs, nonopeptin D, exhibits a broad-spectrum antibiotic activity, including against selected Gram-negative pathogens.

  PublisherOA PDFDOI

• Coenzyme A Tethering Mediates Dehydratase Substrate Promiscuity and Reaction Specificity in Platensimycin, Platencin, and Platensilin Biosynthesis

  Biochemistry · 2025-07-16

  articleOpen accessSenior authorCorresponding

  Biosynthetic studies of the platensimycin (PTM), platencin (PTN), and platensilin (PTL) family of natural products have revealed numerous insights into the chemistry and enzymology of diterpenoid biosynthesis. A deeper understanding of the PTM biosynthetic machinery would advance fundamental knowledge in natural product biosynthesis and facilitate future efforts to exploit these compounds as potential leads for biomedical applications. Herein, we report the functional characterization of the ptmU1 gene that encodes the dehydratase responsible for the formation of the C6–C7 enone moiety in PTM, PTN, and PTL. In vitro experiments, enabled by the semisynthesis of designer substrates and mimics, reveal that PtmU1 is selective for multiple coenzyme A (CoA)-tethered substrates but specific only to the (7R)-hydroxyl group for dehydration. A combination of kinetics analyses, targeted mutagenesis, and in silico docking studies identifies an arginine-rich structural element of PtmU1 that acts as a dynamic CoA-binding anchor, revealing a unique strategy for CoA binding that presumably contributes to the substrate promiscuity and dehydration specificity of PtmU1. Finally, a bioinformatics investigation identifies PtmU1 homologues bearing this CoA-binding motif, suggesting that the observed biosynthetic chemistry might be broadly distributed. Taken together, these results shed new insights into PTM, PTN, and PTL biosynthesis and reveal a new perspective on the role of CoA in substrate binding and enzyme catalysis.

  PublisherOA PDFDOI

• Development of platensimycin, platencin, and platensilin overproducers by biosynthetic pathway engineering and fermentation medium optimization

  Journal of Industrial Microbiology & Biotechnology · 2024-01-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  The platensimycin (PTM), platencin (PTN), and platensilin (PTL) family of natural products continues to inspire the discovery of new chemistry, enzymology, and medicine. Engineered production of this emerging family of natural products, however, remains laborious due to the lack of practical systems to manipulate their biosynthesis in the native-producing Streptomyces platensis species. Here we report solving this technology gap by implementing a CRISPR-Cas9 system in S. platensis CB00739 to develop an expedient method to manipulate the PTM, PTN, and PTL biosynthetic machinery in vivo. We showcase the utility of this technology by constructing designer recombinant strains S. platensis SB12051, SB12052, and SB12053, which, upon fermentation in the optimized PTM-MS medium, produced PTM, PTN, and PTL with the highest titers at 836 mg L-1, 791 mg L-1, and 40 mg L-1, respectively. Comparative analysis of these resultant recombinant strains also revealed distinct chemistries, catalyzed by PtmT1 and PtmT3, two diterpene synthases that nature has evolved for PTM, PTN, and PTL biosynthesis. The ΔptmR1/ΔptmT1/ΔptmT3 triple mutant strain S. platensis SB12054 could be envisaged as a platform strain to engineer diterpenoid biosynthesis by introducing varying ent-copalyl diphosphate-acting diterpene synthases, taking advantage of its clean metabolite background, ability to support diterpene biosynthesis in high titers, and the promiscuous tailoring biosynthetic machinery. ONE-SENTENCE SUMMARY: Implementation of a CRISPR-Cas9 system in Streptomyces platensis CB00739 enabled the construction of a suite of designer recombinant strains for the overproduction of platensimycin, platencin, and platensilin, discovery of new diterpene synthase chemistries, and development of platform strains for future diterpenoid biosynthesis engineering.

  PublisherOA PDFDOI

Recent grants

• Novel Enediyne-Based Antibody-Drug Conjugates for Cancers

  NIH · $4.6M · 2016–2029

• Genome Mining for Enediyne Natural Products from Actinomycetals

  NIH · $1.9M · 2016–2019

• NIH Grant R56AI079070

  NIH · $363k · 2012

• NIH Grant R01CA094426

  NIH · $1.5M · 2008

• NIH Grant P41GM086184

  NIH · $1.1M · 2013

Frequent coauthors

• Dong Yang

  94 shared

• Jianhua Ju

  Shandong University

  73 shared

• Sheng‐Xiong Huang

  Chengdu University of Traditional Chinese Medicine

  66 shared

• Yanwen Duan

  66 shared

• Yong Huang

  58 shared

• David E. Olson

  Multidisciplinary Association for Psychedelic Studies

  55 shared

• Jared T. Shaw

  55 shared

• Jeffrey D. Rudolf

  China Pharmaceutical University

  51 shared