About

Professor Jean Chmielewski is the Alice Watson Kramer Distinguished Professor of Chemistry at Purdue University. His research focuses on the development and application of chemical techniques to understand biological systems, with particular emphasis on biomolecular interactions and the design of novel chemical tools for biological investigation. His work contributes to advancing knowledge in chemical biology and biochemistry, supporting innovations in biomedical research and therapeutic development.

Research topics

• Biology
• Biochemistry
• Chemistry
• Pharmacology
• Engineering
• Nanotechnology
• Microbiology
• Biophysics
• Genetics
• Cancer research
• Computational biology
• Medicine
• Materials science

Selected publications

• Functionalized Coiled-Coil Peptide Nanocrystals for Cellular Protein Delivery

  Chemistry of Materials · 2026-02-26

  articleSenior authorCorresponding

  Peptide-based crystalline nanomaterials with a well-defined growth mechanism remain an unexplored avenue for efficient cellular protein delivery. Herein, we report the formation of Ni(II)-promoted coiled-coil peptide nanocrystals that demonstrate periodic banding and open hexagonal packing. Mechanistic experiments provide insights into the thermodynamic and kinetic interactions involved in crystal growth. Further, metal–ligand interactions facilitate protein inclusion within the crystals, and surface modification with a His-tagged cell-penetrating peptide was harnessed to achieve enhanced protein delivery to cells. As such, an understanding of coiled-coil interactions in nanocrystals may enable the development of modular morphologies via controlled crystal growth with an expansion of biomedical applications.

  PublisherDOI

• Hierarchical Assembly of a Tetrameric Coiled‐Coil Into Cuboid Structures

  Peptide Science · 2025-01-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  ABSTRACT A tetrameric coiled‐coil peptide, TetNL , is used herein as a building block for hierarchical assembly into higher order structures. Assembly within phosphate buffer (pH 7.4) led to the rapid formation of micron‐sized fibers and cuboid structures, a process that could be shifted toward cuboid formation with agitation during the assembly process. Investigation of the packing of the cuboid assemblies by TEM demonstrated a regular banding pattern (4.6 nm) within the structures that was perpendicular to the length of the cuboids, a value that supports an end‐to end organization of the tetrameric coiled coils along the blocks. SWAXS analysis supports that the internal packing of the tetrameric coiled coil building blocks is a close‐packed hexagonal structure. These data represent an interesting comparison with a trimeric coiled coil peptide, TriNL , that forms hollow nanotubes with the same internal hexagonal packing. Modified TriNL has been used to generate numerous unique morphologies, and the data presented herein provide a distinct tetrameric building block that can also be exploited in this manner.

  PublisherOA PDFDOI

• Effects of Rigidity and Configuration of Charged Moieties within Cationic Amphiphilic Polyproline Helices on Cell Penetration and Antibiotic Activity

  ACS Infectious Diseases · 2024-07-26 · 3 citations

  articleSenior authorCorresponding

  Effective molecular strategies are needed to target pathogenic bacteria that thrive and proliferate within mammalian cells, a sanctuary inaccessible to many therapeutics. Herein, we present a class of cationic amphiphilic polyproline helices (CAPHs) with a rigid placement of the cationic moiety on the polyproline helix and assess the role of configuration of the unnatural proline residues making up the CAPHs. By shortening the distance between the guanidinium side chain and the proline backbone of the agents, a notable increase in cellular uptake and antibacterial activity was observed, whereas changing the configuration of the moieties on the pyrrolidine ring from cis to trans resulted in more modest increases. When the combination of these two activities was evaluated, the more rigid CAPHs were exceptionally effective at eradicating intracellular methicillin-resistant Staphylococcus aureus (MRSA) and Salmonella infections within macrophages, significantly exceeding the clearance with the parent CAPH.

  PublisherDOI

• Metal-Promoted Higher-Order Assembly of Disulfide-Stapled Helical Barrels

  Nanomaterials · 2023-09-26 · 1 citations

  articleOpen accessSenior authorCorresponding

  Peptide-based helical barrels are a noteworthy building block for hierarchical assembly, with a hydrophobic cavity that can serve as a host for cargo. In this study, disulfide-stapled helical barrels were synthesized containing ligands for metal ions on the hydrophilic face of each amphiphilic peptide helix. The major product of the disulfide-stapling reaction was found to be composed of five amphiphilic peptides, thereby going from a 16-amino-acid peptide to a stapled 80-residue protein in one step. The structure of this pentamer, 5HB1, was optimized in silico, indicating a significant hydrophobic cavity of ~6 Å within a helical barrel. Metal-ion-promoted assembly of the helical barrel building blocks generated higher order assemblies with a three-dimensional (3D) matrix morphology. The matrix was decorated with hydrophobic dyes and His-tagged proteins both before and after assembly, taking advantage of the hydrophobic pocket within the helical barrels and coordination sites within the metal ion-peptide framework. As such, this peptide-based biomaterial has potential for a number of biotechnology applications, including supplying small molecule and protein growth factors during cell and tissue growth within the matrix.

  PublisherOA PDFDOI

• Metal-Assembled Collagen Peptide Microflorettes as Magnetic Resonance Imaging Agents

  Molecules · 2023-03-26 · 1 citations

  articleOpen accessSenior authorCorresponding

  Magnetic resonance imaging (MRI) is a medical imaging technique that provides detailed information on tissues and organs. However, the low sensitivity of the technique requires the use of contrast agents, usually ones that are based on the chelates of gadolinium ions. In an effort to improve MRI signal intensity, we developed two strategies whereby the ligand DOTA and Gd(III) ions are contained within Zn(II)-promoted collagen peptide (NCoH) supramolecular assemblies. The DOTA moiety was included in the assembly either via a collagen peptide sidechain (NHdota) or through metal–ligand interactions with a His-tagged DOTA conjugate (DOTA-His6). SEM verified that the morphology of the NCoH assembly was maintained in the presence of the DOTA-containing peptides (microflorettes), and EDX and ICP-MS confirmed that Gd(III) ions were incorporated within the microflorettes. The Gd(III)-loaded DOTA florettes demonstrated higher intensities for the T1-weighted MRI signal and higher longitudinal relaxivity (r1) values, as compared to the clinically used contrast agent Magnevist. Additionally, no appreciable cellular toxicity was observed with the collagen microflorettes loaded with Gd(III). Overall, two peptide-based materials were generated that have potential as MRI contrast agents.

  PublisherOA PDFDOI

• Recent advances in coiled-coil peptide materials and their biomedical applications

  Chemical Communications · 2022 · 22 citations

  Senior authorCorresponding
  • Nanotechnology
  • Materials science
  • Computational biology

  Extensive research has gone into deciphering the sequence requirements for peptides to fold into coiled-coils of varying oligomeric states. More recently, additional signals have been introduced within coiled-coils to promote higher order assembly into biomaterials with a rich distribution of morphologies. Herein we describe these strategies for association of coiled-coil building blocks and biomedical applications. With many of the systems described herein having proven use in protein storage, cargo binding and delivery, three dimensional cell culturing and vaccine development, the future potential of coiled-coil materials to have significant biomedical impact is highly promising.

  PublisherDOI

• Co-assembled Coiled-Coil Peptide Nanotubes with Enhanced Stability and Metal-Dependent Cargo Loading

  ACS Omega · 2022-06-10 · 6 citations

  articleOpen accessSenior authorCorresponding

  Peptide nanotube biomaterials are attractive for their range of applications. Herein, we disclose the co-assembly of coiled-coil peptides, one with ligands for metal ions that demonstrate hierarchical assembly into nanotubes, with spatial control of the metal-binding ligands. Enhanced stability of the nanotubes to phosphate-buffered saline was successfully accomplished in a metal-dependent fashion, depending on the levels and placement of the ligand-containing coiled-coil peptide. This spatial control also allowed for site-specific labeling of the nanotubes with His-tagged fluorophores through the length of the tubes or at the termini, in a metal-dependent manner.

  PublisherDOI

• A refined photo‐switchable cyclic peptide scaffold for use in β‐turn activation

  Peptide Science · 2022-03-18

  articleOpen accessSenior authorCorresponding

  Abstract The ability to reversibly modulate peptide secondary structures, such as the β‐turn, allows for precise control of biological function, including protein interactions. Herein, we describe the design of two scaffolds containing an azobenzene moiety with flanking alanine or β‐alanine residues to probe essential features for photo‐control of a β‐turn within a cyclic peptide. To efficiently cyclize the designed linear peptides, prior isomerization of the azobenzene‐containing amino acid from the trans to the cis form was necessary. The two cyclic peptides (TAp and TApβ) were found to undergo rapid photochemical conversion to the cis isomer of the azobenzene, with a more gradual thermal reversion to the trans isomer over the course of a week at 37 °C. Spectroscopic analysis and restrained molecular dynamics simulation of the cis form of TAp and TApβ revealed type II and type II' β‐turns within the cyclic peptides, respectively. The trans isomer of the TAp cyclic peptide was found to have a kink within the peptide structure, whereas the longer trans‐TApβ contained a more extended conformation. TApβ, therefore, demonstrates a clearer difference in the cyclic peptide conformations when in the cis versus trans form, a feature that may prove beneficial for use with biologically active β‐turn sequences.

  PublisherOA PDFDOI

• Supramolecular Assembly of His-Tagged Fluorescent Protein Guests within Coiled-Coil Peptide Crystal Hosts: Three-Dimensional Ordering and Protein Thermal Stability

  ACS Biomaterials Science & Engineering · 2022-04-04 · 4 citations

  articleOpen accessSenior authorCorresponding

  The use of biomaterials for the inclusion and stabilization of biopolymers is an ongoing challenge. Herein, we disclose three-dimensional (3D) coiled-coil peptide crystals with metal ions that include and overgrow His-tagged fluorescent proteins within the crystal. The protein guests are found within two symmetry-related growth sectors of the crystalline host that are associated with faces of the growing crystal that display ligands for metal ions. The fluorescent proteins are included within this "hourglass" region of the crystals at a notably high level, display order within the crystal hosts, and demonstrate sufficiently tight packing to enable energy transfer between a donor-acceptor pair. His-tagged fluorescent proteins display remarkable thermal stability to denaturation over extended periods of time (days) at high temperatures when within the crystals. Ultimately, this strategy may prove useful for the prolonged storage of thermally sensitive biopolymer guests within a 3D crystalline matrix.

  PublisherOA PDFDOI

• The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors

  Cancer Drug Resistance · 2021 · 67 citations

  • Pharmacology
  • Biology
  • Cancer research

  The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture. These findings initially created great excitement in the medical oncology community, as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients. However, clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due, in part, to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance (MDR) in the cancers examined. The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors. Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites. These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters. As such, although possible pharmacokinetic interactions would need to be evaluated, these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers. Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2, which serve a protective role at various blood-tissue barriers. Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents, respectively.

  PublisherOA PDFDOI

Recent grants

• Design of Functionalized Collagen Peptide Supramolecular Assemblies

  NSF · $404k · 2012–2016

• NIH Grant R01GM052739

  NIH · $1.4M · 2004

• NIH Grant R29GM046936

  NIH · $498k · 1997

• Cationic Amphiphilic Polyproline Helices (CAPHs): Coupling Antibacterial Activity with Mammalian Cell Penetration

  NSF · $597k · 2014–2018

• Cationic Amphiphilic Polyproline Helices (CAPHs): Coupling Antibacterial Activity with Mammalian Cell Penetration

  NSF · $671k · 2018–2022

Frequent coauthors

• Reena Zutshi

  Luceome Biotechnologies (United States)

  28 shared

• Bart Kahr

  New York University

  23 shared

• Scott Lovell

  University of Kansas

  21 shared

• Christine A. Hrycyna

  University of California, San Diego

  17 shared

• Christine A. Mitchell

  Omaha VA Medical Center

  17 shared

• P. J. Savickas

  Takeda (United States)

  16 shared

• J. Anand Subramony

  AstraZeneca (United States)

  16 shared

• Jerry J Lewis

  Indiana University – Purdue University Indianapolis

  16 shared

Labs

• Wetherill Laboratory of ChemistryPI