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AI/Machine Learning with Peptides Workshop
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Goran Mausa
Associate professor, University of Rijeka, Faculty of Engineering

AI/Machine Learning Workshop

Abstract

Machine learning is changing the fundamental concepts of discovery in all scientific disciplines, and peptide chemistry is no exception. From classifiers that predict peptide function, to generative models that try to navigate a vast search space of peptide sequences, machine learning is very successful in knowledge discovery from experimentally verified data. In this process, intelligent algorithms are not merely competing with human experts, but they are mainly used to complement our understanding of complex phenomena.
The lack of transparency of many machine learning models and the complex mathematical principles that govern them are the reason why some researchers still do not completely accept their use. Although computer scientists made an effort to allow for a rather simple use of machine learning models, it is essential to understand the importance of data preparation and pre-processing, and the basic concepts of training, validating and testing of these models.
This talk aims at breaking common misconceptions which hinder the application of machine learning to peptide chemistry, explaining its capabilities and limitations and providing examples of good practices. The following challenges will be addressed: (i) the reliability and ability to generalize knowledge, as a paramount concern of any prediction model, (ii) the means of transforming the data into machine-readable format and selecting the essential features, (iii) the amount of data needed to properly train a machine learning model and (iv) the generative capabilities of neural network-based models that overcome the intractability of exhaustive search.

Bio

Goran Mauša is a computer scientist and an associate professor at the Faculty of Engineering, University of Rijeka in Croatia and head of Computer Science department. His research is focused on developing reliable and accurate prediction models based on machine learning, algorithmic solutions for optimization and generative AI models with application primarily in the field of peptides, but also environmental engineering, software engineering and robotics. His work about the development of a generative AI model for reshaping the discovery of self-assembling peptides was recently published in Nature Machine Intelligence. Goran participated in 20 research projects, supervised over 50 defended master and bachelor theses and 1 PhD thesis, and received the national annual award for research excellence in 2022.

Drug Delivery
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Zhigao Niu
Senior Scientist & Innovation Lead, Novo Nordisk

Efforts to improve the SNAC-based formulations for oral peptide delivery

Abstract

The current strategy for oral peptide delivery relies on the use of permeation enhancers (PEs). Despite the clinical success of a few peptide drug candidates, their overall bioavailability remains suboptimal. Our experience indicates that the local concentration of PEs is critical for enhancing the absorption of therapeutic peptides. However, most PEs are derived from fatty acids, which have limited solubility under physiological conditions. An example of this is SNAC, the enhancer utilized in the oral Semaglutide product.
To address the solubility issues associated with SNAC, we have explored various approaches while also aiming to promote a rapid onset of action to improve the current dosing conditions. We have assessed both liquid formulations, such as ionic liquids, and new solid tablet formulations in preclinical setups. The promising candidate has since been progressed to clinical evaluation. Additionally, factors that are likely to influence the performance of PE-based formulations as well as those contributing to clinical translatability issues will be shared.

Bio

Zhigao Niu holds a PhD (2016) in Pharmaceutical Science from the University of Santiago de Compostela, where his research focused on polymer and lipid-based nanoparticles for oral peptide delivery. Currently, Zhigao works at Novo Nordisk as Senior Scientist and Innovation Lead, responsible for external collaborations on new technologies covering oral biologics, long-acting injectables, high-dose/high-viscosity formulations, and tissue targeting, among others.
Zhigao's expertise and research interest involves advanced drug delivery systems and drug-device combinations for proteins, peptides and nucleic acids. He is an inventor of 3 patent families, and his work has been published in top pharmaceutical journals including the Journal of Controlled Release, Advanced Materials, ACS Nano, Advanced Drug Delivery Reviews. He is currently on the editorial board of Drug Delivery and Translational Research, and serves as peer reviewer for over 20 journals.

Chemistry of Complex Peptides
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Christian Gruber
Assoc. Prof., Medical University of Vienna

Peptide-based approaches to GPCR drug discovery: novel κ-opioid receptor ligands for applications in inflammatory pain

Abstract

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and key regulators of physiological processes, making them prime targets for therapeutic intervention. Among them, opioid receptors play a central role in pain modulation, with the κ-opioid receptor (KOR) emerging as a promising target for the development of safer analgesics that avoid the addictive potential of traditional µ-opioid drugs. Despite their therapeutic potential, peptide-based GPCR ligands face challenges such as poor metabolic stability, short half-life, and low oral bioavailability, necessitating innovative drug design strategies.

To overcome these limitations, we integrate multiple approaches, including evolutionary peptide mining from genomes and transcriptomes, as well as pharmacology-guided screening of nature-derived peptide extracts, to identify novel GPCR ligands. Using advanced chemical and computational techniques - such as molecular grafting, backbone cyclization, cysteine stapling, and de novo design - we have engineered peptide ligands with improved stability and pharmacodynamic properties. Specifically, our work focuses on the development of next-generation KOR agonists with tailored signaling profiles to mitigate side effects and enhance therapeutic efficacy. As a proof-of-concept, lead candidates have demonstrated analgesic and anti-inflammatory effects in vivo, highlighting their potential for the treatment of chronic pain syndromes, including peripheral pain and inflammatory bowel disease.

Bio

Christian Gruber is research group leader and Associate Professor at the Medical University of Vienna (Austria). He studied Biochemistry at the University of Tübingen (Germany) and received a Ph.D. in Molecular Biosciences from The University of Queensland (Australia). His research focus to study biological function, structure-activity relationship and pharmacological mechanism of nature-derived peptides isolated from plants and invertebrates (e.g., peptide hormones, neuropeptides and peptide toxins), and the development of novel peptide therapeutics, especially as ligands of G protein-coupled receptors.
Further information: www.gruber-lab.com

For his research achievements he won several awards such as the EFMC Prize for a Young Medicinal Chemist in Academia, European Federation for Medicinal Chemistry (2017), Dr. Willmar Schwabe-Award, Society for Medicinal Plant and Natural Product Research (2014), IUPHAR Young Investigator Silver Award, International Union of Basic and Clinical Pharmacology (2014) and the Heribert-Konzett Award, Austrian Pharmacological Society (sponsored by Astra Zeneca, 2013)
He has memberships and functions in scientific organizations such as the Austrian Peptide Community (founder and co-chair), Herbal Medicinal Products Platform Austria (vice-president) and the “Max-Bergmann-Kreis” – German-speaking association to promote peptide chemistry research (member elect). He is Associate Editor of the British Journal of Pharmacology and Editorial Board Member of the Journal of Medicinal Chemistry.

As co-founder and chief scientific officer of Pepdura AB (www.pepdura.com), he is involved in translation and the development of stabilized peptides for applications as GPCR ligands.

Chemistry of Complex Peptides
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Tom Tucker
Principal Scientist, Merck and Co., Inc.

Discovery of the Highly Potent and Orally Bioavailable Cyclic Peptide PCSK9 Inhibitor MK-0616

Abstract

Modalities Chemistry Group, Department of Medicinal Chemistry, Merck & Co, Inc., West Point, PA 19486, USA
Proprotein convertase subtilisin-like/Kexin type 9 (PCSK9) is a clinically well-validated and critically important target for treating high LDL-cholesterol and potential coronary artery disease. Two antibody-based and one siRNA based anti-PCSK9 therapeutics have been approved by the FDA for treating high LDL-cholesterol levels and have demonstrated excellent clinical efficacy for lowering LDL levels and preventing adverse cardiac events. However, all of these therapies are parenterally delivered and to date an efficacious, orally dosed anti-PCSK9 therapeutic has not been approved. We focused our efforts on discovering and optimizing novel, orally bioavailable cyclic peptide agents based on leads derived from an mRNA display screening campaign. From the mRNA display screening, we were able to identify moderately potent inhibitor leads. Guided by structural data, we were able to optimize our early leads to enhance metabolic stability, potency, and engineer out several unfavorable off-target activities to provide advanced next generation development candidates. Using an enabled formulation-based approach, we demonstrated acceptable oral bioavailability and good overall pharmacokinetics for these molecules, and using a Target Engagement assay were able to build clear PK/PD relationships in primates. Final optimization of candidate molecules to address formulation-related issues led to the discovery of MK-0616, which is currently undergoing clinical investigation as an LDL-cholesterol-lowering agent. In this talk, we will detail the systematic optimization of these molecules guided by structural data, leading to the discovery of the clinical compound.

Bio

After completing my education, I joined the Medicinal Chemistry Department of Rorer Central Research (now a part of Sanofi-Aventis) in 1984. In 1989, I moved to Merck Research Laboratories in West Point, PA. I began my career at Merck working in the peptide/peptidomimetic space, transitioned into small molecule therapeutics for about 17 years, then moved on to conjugate based siRNA Delivery, and finally then back into the peptide drug discovery space in 2012. I am currently a Principal Scientist in the Peptide /Modalities Drug Discovery Team at MRL West Point. I am the author/co-author of over 50 publications, an inventor on over 70 patents, and have presented frequently at various external meetings. During my career, I have been directly associated with two molecules that have become FDA approved drugs, both in the HIV antiviral therapeutic space: the first-generation non-nucleoside reverse transcriptase inhibitor StocrinTM / SustivaTM (Efavirenz); and the second-generation non-nucleoside reverse transcriptase inhibitor PifeltroTM (Doravirine). I also was a key contributor to the design and synthesis of MK-0616, an oral cyclic peptide therapeutic that is currently undergoing Ph 3 clinical trials. My current research interests are focused on the design and development of novel peptide therapeutics.

Self-assembling peptides that respond to environmental stimulus, particularly pH fluctuations, are gaining significant attention for their potential use in a wide range of biomedical and biotechnological applications. These stimuli-responsive materials can adapt to varying pH conditions, which is crucial in systems such as drug delivery, biosensing, and tissue engineering. However, the design of pH-sensitive peptide assemblies has been limited by the lack of naturally occurring amino acids that exhibit the required pH responsiveness within the relevant biological range. To address this, we have developed a novel strategy that incorporates non-natural amino acids with ionizable side chains into peptide assemblies. These amino acids, specifically designed with tertiary amine groups, undergo pH-dependent ionization, allowing for the fine-tuning of the peptide’s behavior in response to environmental pH changes. Our experimental and computational results show that these ionizable residues integrate smoothly into the peptide structure, influencing the assembly's stability and disassembly at specific pH thresholds. Additionally, the incorporation of these non-natural amino acids enhances the peptides' functionality, such as their ability to disrupt bacterial membranes at acidic pH, offering potential applications in antimicrobial therapies. This new approach to designing pH-responsive peptide materials provides enhanced control over their properties, opening the door for their use in advanced drug delivery systems, sensors, and other bio-tech applications.

Post-translational modifications (PTMs) are essential regulators of cellular processes, influencing gene expression, protein stability, and protein-protein interactions.1 Among these, lysine and arginine modifications such as acetylation, methylation, citrullination and other acylation variants are key players in epigenetic regulation.2,3 However, the development of assay systems that can adapt to a wide range of PTMs remains a challenge. Here, we present a generalized fluorescent turn-on platform that utilizes simple peptide substrates to study the installation and removal of a diverse set of lysine and arginine PTMs, with a focus on epigenetically relevant ones.

In addition to synthetic installation of native post-translationally modified residues in peptides, we employed thialysine and thiaarginine analogs to mimic modified lysine and arginine residues, enabling facile introduction of functional PTM mimetics using simple cysteine chemistry.4,5 We utilize the cleavage of peptidyl lysine and arginine bonds by trypsin, which are only removed when these residues are in their unmodified state. Conversely, in their post-translationally modified state, the peptides remain intact leading to internal fluorescent quenching, making the system adaptable to studies of both writer and eraser enzymes.

Model PTMs that have been studied are removal of lysine acetylation, lactylation and β-hydroxybutyrylation by SIRT3, removal of methylated lysine variants by KDM3A and KDM4A as well as arginine citrullination by PAD4, highlighting the versatility of this approach. By integrating modularity and fluorogenic detection, this system provides an accessible, flexible, efficient, and adaptable tool for PTM studies. Its broad applicability offers significant potential for exploring enzymatic mechanisms, PTM crosstalk, and protein regulation across diverse biological contexts.

References
1. B. S. Sharma, V. Prabhakaran, A. P. Desai, J. Bajpai, R. J. Verma and P. K. Swain, Oncogen, 2019, 2, 12.
2. J. Fuhrmann, K. W. Clancy and P. R. Thompson, Chem. Rev., 2015, 115, 5413-5461.
3. A. H. Shukri, V. Lukinović, F. Charih and K. K. Biggar, Biochim. Biophys. Acta Gene Regul. Mech., 2023, 194990.
4. J. C. J. Hintzen and J. Mecinović, Tetrahedron Lett., 2023, 124, 154602.
5. S. Ofori, H. S. Desai, F. Shikwana, L. M. Boatner, E. R. Dominguez Iii, J. O. Castellón and K. M. Backus, Chem. Commun., 2024, 60, 8856-8859.

mRNA display is a powerful in vitro selection and directed evolution technique that enables the screening of trillions of peptide variants for desired functions in a single experiment. Compared to other display technologies, such as phage display, mRNA display offers distinct advantages, including ultra-high-diversity libraries, in vitro selection, and the ability to incorporate noncanonical amino acids. As a result, mRNA display has become the leading display technique for discovering novel (macrocyclic) peptide binders with antibody-like affinities and even potential oral bioavailability.
PeptiFinder Biotech is the pioneering CRO specializing in mRNA display technology, providing cutting-edge services to the pharmaceutical industry. PeptiFinder mRNA display platform offers various libraries (linear, monocyclic, and bicyclic peptides) with ultra-high-diversity (up to 10^15), which can be readily screened against almost any biological target of interest (6-8 weeks) with a remarkable success rate of over >95%. Furthermore, by incorporating unnatural amino acids into macrocyclic peptide libraries, PeptiFinder mRNA display platform can generate peptide hits with enhanced physiochemical properties and optimized pharmacokinetics, streamlining the process of optimizing lead compounds into clinical candidates and accelerating drug discovery timelines for clients. PeptiFinder also offers customer library service tailored to specific client needs.

Peptide Showcase
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Lauren Cline
BPS manager, BPS

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Company Description

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Bio

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Mandë Holford
Professor, Hunter College - CUNY

Killer Snails: Agents of Change and Innovation

Abstract

Talk abstract still to be determined.

Bio

Mandë Holford is a professor of chemistry at CUNY Hunter College and The CUNY Graduate Center, with scientific appointments at the American Museum of Natural History and Weill Cornell Medicine. Her joint appointments reflect her interdisciplinary research.

Dr. Holford’s research focus is chemical and biological diversity, specifically, investigating venom and venomous organisms as agents of change and innovation in evolution and for therapeutic development in pain and cancer.

She is actively involved in science education, advancing the public understanding of science and science diplomacy. She has received several awards including being named a 2020 Sustainability Pioneer and a 2015 New Champion Young Scientist by the World Economic Forum, and a California Academy of Sciences Fellow. She also received the prestigious Camille Dreyfus Teacher-Scholar Award, an NSF CAREER Award, and was honored as a Breakthrough Women in Science by the Howard Hughes Medical Institute (HHMI) and NPR’s Science Friday. She is cofounder of KillerSnails.com, an award winning EdTech company that uses gaming as a conduit to advance scientific learning in K-12 classrooms. Dr. Holford is a life member on the Council of Foreign Relations and an AAAS Science & Technology Policy Fellow.