All posts in none

The Orbit Peptide Discovery platform allows for the identification of highly efficacious peptide binders. There is renewed interest in the use of peptides as targeting agents for therapeutic delivery, particularly nucleic acid (eg siRNA) or radiopharmaceuticals. These peptides bind to specific disease or tissue specific biomarkers to allow for targeted action of a conjugated payload. Transferrin Receptor 1 (TfR1) has been a hotly pursued target, due to its ability to transcytose payloads across the Blood-Brain Barrier (BBB) for therapeutic delivery within the central nervous system. Its additional expression on the surface of muscle cells has also been exploited to deliver corrective nucleic acid in the treatment of Duchenne Muscular Dystrophy (DMD). Orbit has sought to leverage its unique affinity screening technology to identify novel peptide binders to TfR1. Subsequent validation in cells demonstrates that these peptides specifically bind TfR1 and bind in a manner non-competitive to the binding of transferrin. These hit peptides represent an ideal starting point for further development towards novel TfR1 specific treatments. ​

AI/Machine Learning with Peptides Workshop
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Nicolai Ree
Research Scientist, Gubra

AI/Machine Learning Worshop

Abstract

Peptides have emerged as an effective therapeutic modality for a broad spectrum of indications, including obesity. From a drug discovery perspective peptides offer attractive properties such as high receptor potency and selectivity, as well as a potential for long circulating half-life. Historically, the development of peptide-based drugs has been based on endogenous hormones; however, this approach is not applicable to targets without an identified native peptide ligand.

To address this challenge, we have implemented an AI-based computational pipeline for the de novo design of peptide binders. This pipeline allows for the specification of hotspot residues on the target protein and generates peptide sequences by maximizing hotspot proximity and employing structural metrics from AlphaFold2 [1] and proteinMPNN [2]. The predicted peptide binders show high structural diversity and virtually no sequence identity to known sequences.

We experimentally validated our AI-based strategy by synthesizing and functionally characterizing 190 de novo designed peptides targeting the active site of a G protein-coupled receptor (GPCR). Functional assays revealed receptor activity for 74% of these peptides, with the most potent hits exhibiting an IC₅₀ of 34 nM (antagonist) and an EC₅₀ of 3.2 μM (agonist). Subsequently, we optimized these de novo hits through deep mutational scans and machine learning (ML)-guided structure-activity relationship (SAR) analyses,[3] and identified several mutations that increased potency.

In summary, this study experimentally validates an AI-based pipeline for the de novo design of peptide therapeutics and demonstrates the application of ML-guided optimization to enhance drug properties. The results serve as a proof of concept for the integration of AI methodologies in peptide drug discovery, enabling the development of novel therapeutics towards previously undruggable targets in a cost-effective and time-efficient manner.

References:
[1] J. Jumper et al., Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021). DOI:10.1038/s41586-021-03819-2
[2] J. Dauparas et al., Robust deep learning–based protein sequence design using ProteinMPNN. Science 378, 49-56 (2022). DOI:10.1126/science.add2187
[3] J.C. Nielsen et al., Machine-learning-guided peptide drug discovery: Development of GLP-1 receptor agonists with improved drug properties. J. Med. Chem., 67 (14), 11814–11826 (2024). DOI:10.1021/acs.jmedchem.4c00417

Bio

Research Scientist in Computational Drug Discovery at Gubra working on peptide-based drug discovery with a focus on peptide design, screening and ML-driven analysis of large peptide libraries. Gubra is a CRO and biotech company specialized in high-end preclinical contract research and peptide-based drug discovery within metabolic and fibrotic diseases.

Prior to Gubra: PhD and later postdoctoral researcher at Bayer AG and Department of Chemistry, University of Copenhagen. This work focused on bridging quantum chemistry calculations and machine learning for molecular property predictions, in silico molecular design and computational retrosynthetic planning, especially focusing on regioselectivity and chemical stability.

Peptide Showcase
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Justin Northrup
Head of R&D, ThirdLaw Molecular

Application of a 4.5 Billion Member DNA Encoded Library of Spiroligomer[TM] Macromolecules to Discover Low Nanomolar Binders for TNF-alpha

Company Description

Constrained peptides have garnered significant attention due to their potential to target proteins that are undruggable by small molecules. Innovations in this space will allow for targeting of challenging biological pathways, disrupting protein-protein interactions, and modulating immune responses. We have developed a highly advanced form of constrained peptide called Spiroligomer™ peptidomimetics – a class of synthetic peptidomimetics characterized by stable, spirocyclic structures which combine the versatility of peptides with preorganization that comes from their poly-cyclic fused-ring structure. The unique structure of Spiroligomer molecules provides them with several advantages over other approaches, including high affinity and specificity to a wide range of targets, immunity to proteolysis, and inherent cell permeability. We have synthesized a DNA encoded library (DEL) of 4.5 billion Spiroligomer™ macromolecules and screened it against more than a dozen proteins. From these initial screens, we have validated low nanomolar binding to multiple proteins of interest, including TNF-alpha and RCA-Lectin (a protein with ~85% homology to Ricin).

Bio

I'm the Head of R&D and Principal Scientist at ThirdLaw Molecular, having been with the company since it's founding in 2020. I received my BA in chemistry from Kalamazoo College in 2009, and I received my PhD in Organic Chemistry from Temple University in 2016, authoring numerous papers on the development of Spiroligomer molecules and their related chemistries. I moved on to a postdoc in chemical biology and radiochemistry with Dr. Mark Sellmyer in the Department of Radiology at the University of Pennsylvania. I've worked on Spiroligomer[TM] molecules since 2010.

Peptide Showcase
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Benyi Li
Professor, KANSAS UNIV MEDICAL CENTER

An AR protein degrader for prostate cancer therapy

Company Description

Prostate cancers in the late stage after androgen deprivation therapy plus anti-androgen treatment with Xtandi (a.k.a. Enzalutamide or MDV3100) or Zytiga. (a.k.a. Abiraterone) often become treatment-resistant without any means to cure. Recent studies from our group and others revealed that eliminating AR protein (full-length or truncated) will overcome treatment resistance in advanced prostate cancers. Although the recently reported PROTAC approach can enhance AR protein degradation, it is not suitable for patients who harbor a truncated AR protein that escapes PROTAC-mediated degradation. Our preliminary studies identified a small peptide that triggers the androgen receptor protein (including full-length and truncated variants) degradation in prostate cancer cells. In this talk, I will discuss the optimization of small peptide to improve its drug-like properties. We will show the results of our investigation in multiple prostate cancer cell lines-derived animal xenograft models, and patient tissue-derived xenograft models in animals. We will confirm the therapeutic efficacy of the optimized peptides in promoting AR protein degradation in animal models. I will also show how this peptide triggers AR protein degradation based on our strong preliminary data that AR stability was attenuated due to the small peptide-induced disruption of AR association with a protein complex of PHKA1 and PHKB. The novel therapeutic peptide will provide new hope for patients who developed anti-AR drug resistance.

Bio

Dr. Li received his medical education in China and Ph.D. work in Japan. After moved to the US in 1998, he stayed away from clinical work but focused on urological research. After 2 postdoc fellowships at Moffitt Cancer Center and Baylor College of Medicine, he joined the KUMC Urology faculty at the end of 2001 and established the basic research program for the department. His research topic is mainly on prostate cancer, aiming to develop novel and clinically beneficial therapeutics for patients with advanced prostate cancers.

Anthony Silvestri
Head of Chemistry, Unnatural Products

Tales of macrocycle medchem: leveraging peptide discovery and optimization technologies

Abstract

Peptide DNA-encoded libraries (DEL) benefit from superior chemical control relative to ribosome display technologies and can be tailored to yield de novo peptide ligands with favorable physicochemical properties as well as high target affinities. This presentation will discuss a DEL design and workflow that yielded a neutral cyclic peptide with nM affinity to MDM2 and juxtapose it against a separate internal optimization effort of a rationally designed chemical series also targeting MDM2. We took a non-traditional medicinal chemistry approach to lead series optimization and, by leveraging our in-house parallel synthetic and computational platform, were able to make large jumps through scaffold and pharmacophore space. This allowed us to imbue the lead series with the high target affinity and small-molecule-like passive permeability necessary to achieve nM cell activity.

Bio

Tony was born and raised in Southern California and earned a B.S. in Chemistry from Colorado State University. He went on to complete a Ph.D. in Organic Chemistry at Scripps Research with Phil Dawson, where he developed novel organometallic peptide ligation and macrocyclization techniques. Since joining Unnatural Products Inc. in 2019—shortly after its founding—Tony has led the chemical development side of the company's peptide macrocycle optimization platform.

Andre Watson
Chairman and CEO, Ligandal

Peptides for Use in Targeting Payloads

Abstract

Abstract for this talk coming soon!

Bio

I am Founder and CEO of Ligandal, a genetic medicine company that uses nanotechnology to develop predictive targeted delivery systems as the roadway to personalized therapies.

We are a precision medicine biotechnology company with a broadly applicable technology that can be tailored to a variety of cell & gene therapy needs. The company’s mission is to enable precision and personalized medicine on a global scale.

Given that increasingly complex disease states require precise and custom-tailored medicine, much of our technology development has focused on combining gene therapy with targeting peptides to enable completely new paradigms in evolutionary medicine. My expertise lies in targeted gene delivery, nano- and biomaterials, computational modeling of peptides, binding simulations, immunoengineering, as well as CRISPR and TALEN based gene editing. At Ligandal, we have demonstrated peptide-based delivery of CRISPR, RNA, DNA, siRNA, and a range of genes or proteins to virtually any cell type.

My formal background is in Biomedical Engineering with a focus on Biomaterials Science and gene delivery. I started Ligandal when I was 22 and moved to Silicon Valley to gain support for developing the next generation of medicine. I am an inventor on 80 pending patents (21 granted, 5 allowed, remaining pending) across 16 patent families for AI approaches to discovery of therapeutic compounds, materials science and engineering approaches for drug and gene delivery, next-generation bioengineering techniques, synthetic vaccines, and delivery of nucleic acids and proteins with cell-specific targeting molecules. More recently, much of this work has been computational in nature, where Ligandal has pioneered the field of Predictive Interactomics; the study and engineering of precise targeting ligands for various cells, tissues, and organs. My personal mission is to bring about humanity's prosperity through enabling a world where we can program biological systems at will, and for good.

Outside of work, I am a competitively trained classical pianist and used to compete in powerlifting. Music has a very special place in my heart, and I love playing everything from Beethoven Sonatas to Chopin Ballades. I also love cooking and exploring the world.

To stay up to date with what we are doing, please see our website: www.ligandal.com

Peptides in the Clinic
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Jeff Alberts
Advisor Scientist-ADME, Eli Lilly and Company

The Journey of Bioanalytical Support for Peptides from Target of Interest to Post Market

Abstract

This presentation will share a case study that highlights a bioanalytical strategy to transition peptide biotherapeutics from early discovery through commercial launch. Support for critical in vitro and in vivo ADME and non-GLP toxicology studies will be highlighted along with their associated LC/MS methodologies. For discovery stages, the presentation emphasizes the importance of optimizing instrument cycle time to enhance capacity and reduce data turnaround times. Additionally, the validation of clinical methods to support development-stage studies internationally, including in the US and China, will also be discussed. At the end of the presentation, a summary of pre-clinical and clinical study statistics associated with an NDA submission will be shared.

Bio

Jeff graduated from Michigan State University in 1992, worked as a protein chemist at MSU, and then held various roles at Waters Corporation and Bristol Myer-Squib. He joined Lilly in 2003 as a Biotransformation Structure ID Chemist, later becoming the small molecule bioanalytical lead in 2017, and recently transitioned to leading ADC/AOC bioanalysis.

Peptide Showcase
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Stephane Roche
CEO, AdaptBio Therapeutics

ADAPT: An Emerging Platform of Antibody CDR-H3-based Scaffolds for the Discovery of Novel Classes of Protein-Protein Interaction Inhibitors

Company Description

Aberrant and misregulated protein–protein interactions (PPIs) are implicated in a plethora of human diseases; Yet the development of small-molecule PPI inhibitors continues to lag behind the remarkable success of monoclonal antibody drugs, which dominates this therapeutic space. To enter this space, our team at AdaptBio Inc. has pioneered the ADAPT platform technology (short for Adaptive Design of Antibody Paratopes into Therapeutics) inspired by antibody CDR-H3s to engineer next-generation therapeutic peptides targeting PPIs. In this talk, we will discuss how this scaffolding technology can faithfully miniaturized CDR-H3 antibody-mimics, providing powerful tools to devise chemical probes and preclinical drug candidates to greatly accelerate the discovery of PPI inhibitors, .

Bio

Stéphane is the founder and CEO of AdaptBio Therapeutics (Est. in 2024). He has over 15 years of experience in synthetic and medicinal chemistry in diverse therapeutic areas working on small-molecule natural products and peptide drugs. This rich experience in drug discovery drives his interest in solving complex issues at the interface of science, medicine, and business strategy to create novel medicines that will improve the lives of patients and their families.

Peptide Showcase
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Nicolas Gilles
senior researcher, CEA

A snake peptide toxin for treatment of kidney diseases. From bench to bedside

Company Description

The kidney regulates many physiological roles like water homeostasis, expertly managed by the vasopressin type 2 receptor (V2R). Positioned within the kidney's collecting tubule, this membrane receptor responds to the peptide hormone, the vasopressin. The V2R activation triggers the generation of the secondary messenger cyclic adenosine monophosphate (cAMP). cAMP induces urine concentration in alignment with the body's requirements.
Two pathological conditions, hyponatremia and polycystic diseases are addressed by blocking the V2R and since the 1980s, pharmaceutical enterprises developed the "vaptans". Regrettably, the majority of vaptans exhibited hepatotoxicity concerns, and only the tolvaptan (Otsuka Pharma) is used but with many concerns, leaving millions of untreated patients.
Animal venoms are an extraordinary source of potent and natural peptide toxins. A comprehensive screening of venoms against the V2R led to the revelation of a novel cluster of snake toxins within the Kunitz-type peptide family. Among these, the MQ1 toxin emerged as a standout due to its remarkable pharmacological properties. Evaluation within rodent models of hyponatremia and polycystic diseases revealed its promise. Subsequent efforts involved refining the MQ1's characteristics in term of risk of immunogenicity and affinity. The generated MQ232, a 57 residues peptide reticulated by 3 disulfide bridges and produce by solid phase synthesis, boasts a therapeutic window of over 100. With all the hallmarks of a groundbreaking solution, MQ232 is poised to address unmet medical needs.
Embarking on the path to clinical validation, the startup V4Cure, specializing in leveraging animal toxins within the cardio-renal axis, supports MQ232 into human assessment.

Bio

Full time researcher at the Department of Medicines and Technologies for Health, in the Toxins Receptors and Ion channels team. In charge of the identification and therapeutic development of animal toxins active on G-Protein Coupled Receptors for human benefit.

Dr. Nicolas Gilles is an expert in the study of animal toxins. He is pioneering the investigation of animal toxins acting on GPCRs, the largest therapeutic target class. His strongest expertise lies in therapeutic target identification and all the steps from venom manipulations, to in vivo validation. When the pharmacological properties of these new ligands are deemed exceptional, a lead optimization is realized and its therapeutic development initiates through a dedicated start-up. V4Cure, a CEA spin-off, is currently developing the V4C-232 for kidneys diseases.

Drug Delivery
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Katerina Leftheris
Visiting professor/former CSO, Stony Brook University/Vilya, Inc.

Targeting Peptides and Macrocycles as Drugs: Novel approaches on the Horizon

Abstract

There has been a significant resurgence in the advancement of peptides and macrocycles as therapeutic agents. This has been due in part to four main advances;
- Improved approaches for identifying hits (mRNA display, DEL, ML approaches)
- Discovery of novel approaches to drug delivery (permeation enhancers, sustained release formulations, etc.)
- The drug discovery of unique modalities requiring peptide/macrocycle binders such as drug conjugates and radioligand targeting agents.
- Renewed medicinal chemistry efforts targeting macrocycles/peptides
While these advances have yielded several clinical candidates, there are still significant unsolved challenges that continue to impede the overall drug discovery success rate. Often, the DMTA cycle is too long, in part due to lengthy, often challenging syntheses of peptides/macrocycle analogs off DNA. To improve cycle time, building blocks are often limited to what can be purchased, potentially limiting the diversity of structural motifs tested. The resulting hits frequently have poor ADME properties requiring an extensive medicinal chemistry effort. Also, routine delivery of bioactive peptides/macrocycles inside a cell remains a challenge. This talk will address some of these challenges and what novel approaches are currently in exploratory development. These include:
- The design of polymer-bound peptides that can penetrate a cell and show functional cellular activity as well as in vivo efficacy.
- A macrocycle-payload delivery system targeting the internalization of specific membrane bound proteins
- A machine learning engineered, nonribosomal screening approach that can generate peptides/macrocycles inside a cell

Bio

Dr. Katerina Leftheris is currently a Biotech builder and executive leader. She holds a Visiting Professorship with Stony Brook University, is currently an SAB member and holds Board of Director positions for several biotech companies focused on peptides and macrocycles. She has spent over 25 years in the small molecule/macrocycle drug discovery and early development space from early screening for hits (HTS, DEL) Ph 1 clinical studies. Throughout her career, she and her teams have put 15 compounds into the Clinic spanning many molecular targets including (but not limited to) kinases, GPCR’s, NHR’s, protease inhibitors, E3 ligase modulators/ligand directed degraders, and integrins. These targets cover debilitating diseases in several therapeutic areas including oncology, I/O, immunology, neuroscience, metabolic diseases and fibrosis.
She was most recently the CSO of Vilya Inc, an Arch Ventures-backed biotech company advancing macrocycles as oral drugs using machine learning algorithms first developed by the D. Baker Lab (U. Washington). She built out a full in-house drug discovery team and advanced several targets using ML predictive docking algorithms. Prior, she held multiple positions including SVP for Drug Discovery, Rheos Medicines and VP of Discovery Chemistry at Pliant Therapeutics, While at Pliant, she built and led discovery teams and is co-inventor of multiple integrin inhibitors in the clinic including Bexotegrast, an orally active avb6/1 inhibitor currently in PhIIb/PhIII for Idiopathic pulmonary fibrosis and primary sclerosing cholangitis.
Earlier, Katerina was site-head of Discovery Chemistry for Celgene, San Diego, where she built and led chemistry teams in advancing five novel clinical candidates, including the then nascent degrader approach utilizing glutarimide CRBN binders. Prior, she held positions of increased leadership with Vitae Pharmaceuticals . Earlier in her career, Katerina held positions of increasing responsibility in Discovery Oncology and Immunology Chemistry at Bristol-Myers Squibb.
To date, Katerina has over 140 publications/issued patents. She is an elected ACS division councilor and sits on the Executive Committee of the MEDI division of the American Chemical Society.
Katerina earned her B.A. in chemistry from Smith College, Ph.D. in organic chemistry from the University of California, San Diego and completed an NIH Postdoctoral Fellowship, University of Pennsylvania.