All posts in none

The streptavidin–biotin binding pair is one of the most widely used recognition systems in biotechnology due to its extraordinarily high affinity and the ease of target biotinylation. While indispensable in diagnostic testing, it is limited by interference from endogenous biotin, and therapeutic applications are further complicated by strong immunogenicity. A mirror-image (D-) protein/ligand system offers a potential solution by combining the low immunogenicity of D-proteins with a stereochemically orthogonal system. To explore this, we synthesized both L- and D-streptavidin via a three-segment chemical protein synthesis strategy. Poor solubility of a hydrophobic peptide segment was addressed using our Glu-based AlHx “helping hand” technology, enabling efficient ligation and purification. After segment assembly and a novel high-yield folding protocol, structural integrity was confirmed by circular dichroism and size-exclusion chromatography. Binding analysis by isothermal titration calorimetry revealed an extraordinary 200-million-fold preference for the matched biotin–streptavidin pairs, rendering the D-streptavidin/L-biotin system functionally orthogonal to the natural binding pair. High-resolution X-ray structures of matched and mismatched complexes provided insight into this stereochemical selectivity. These results highlight the extreme stereospecificity of streptavidin–biotin recognition and the power of chemical protein synthesis to access mirror-image biomolecular tools with potential to enhance current diagnostics and enable new therapeutic formats.

Drug Delivery
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Jie Zhang
Director of Chemsitry, Protagonist Therapeutics

PN-881: First-in-Class Oral Peptide Targeting the IL-17 Pathway

Abstract

Protagonist Therapeutics is a discovery through late-stage development biopharmaceutical company. Two novel peptides derived from Protagonist's proprietary discovery platform are currently in advanced Phase 3 clinical development, with New Drug Application submissions to the FDA potentially in 2025. In this showcase, we report one of the pre-clinical assets - PN-881: First-in-Class Oral Peptide targeting the IL-17 pathway, including its pre-clinical potency, metabolic stability, pharmacodynamic and efficacy results. Anticipate Phase 1 to be initiated in the fourth quarter of 2025.

Bio

Jie Zhang is a Director of Chemistry at Protagonist Therapeutics in Brisbane Australia. She has an extensive experience in peptides drug discovery and preclinical development, from peptides design, synthesis, structure-activity relationships to bio-analysis and DMPK optimization. She has been with Protagonist for over 15 years with increasing responsibility and has been a key member of the discovery team for many projects, including two Phase 3 candidates Icotrokinra and Rusfertide, and most recently IL-17 blocker PN-881. She received her Ph.D. in Chemistry from the University of Newcastle.

The Kay Lab specializes in protease-resistant mirror-image (D) peptide drugs, which have increased drug half-life compared to natural L-peptides and reduced host-immune response due to their evasion of MHC presentation. Cholesterol-conjugated PIE12-trimer is a D-peptide HIV entry inhibitor with promising non-human primate efficacy and phase I clinical trial results, but its relatively small size (~9 kDa) leaves it vulnerable to kidney filtration, resulting in a shorter half-life than long-lasting biologics or depot-formulated small molecules. As with all HIV monotherapies, it is ultimately susceptible to viral resistance due to HIV’s high mutation rate. Monoclonal antibodies (mAb) and antibody-drug conjugates (ADC) have seen an increase in therapeutic use due to their high specificity and long half-lives. For HIV, broadly neutralizing antibodies (bNAbs) as a class can bind to a variety of conserved viral envelope epitopes to block infection, but their breadth and potency are not yet sufficient on their own to control or prevent disease. Here, I describe the development of an antibody-D-peptide conjugate (ADpC) comprised of PIE12-trimer and a bNAb in a heterochiral “single-molecule cocktail” that we predict will broadly and potently neutralize HIV with a long half-life to support very infrequent dosing. I am synthesizing this ADpC using sortase-mediated conjugation. Sortase ligates a specific C-terminal sequence motif (LPXTG) to an N-terminal poly-glycine on a second peptide. The bNAb and PIE12-trimer will be connected via a flexible polyethylene glycol (PEG) linker. This ADpC will provide a combination therapy in a single molecule with significant potential therapeutic and pharmacokinetic benefits for patients.

Peptide Showcase
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Eric Fang
Site Head-CSO, Snapdragon Chemistry, a Cambrex Company

Liquid-phase peptide fragment manufacturing technologies and workflows using batch and flow chemistry 

Company Description

“Peptide-based therapeutics are an area of increasing interest within the pharmaceutical industry with an expected compound annual growth rate (CAGR) of ~5.5% over the next 10 years. Recently there has been significant increased interest in these therapies due to the success of GLP-1 receptor agonists for the treatment of diabetes and for weight loss. Currently Solid-Phase Peptide Synthesis (SPPS) is one of the leading manufacturing technology in use for the production of peptides. SPPS, however, suffers from several disadvantages including large amounts of solvent waste and the requirement of more specialized equipment resulting in manufacturing capacity limitations. Liquid phase peptide synthesis (LPPS) offers an attractive alternative approach with dramatic reductions in PMI and the ability to use traditional batch reactors. Snapdragon has developed two distinct LPPS processes for the production of peptide fragments in standard batch reactor and flow chemistry to support downstream solution-phase fragment coupling. These processes have now been demonstrated on multi-kilogram scale and provide an order of magnitude reduction in PMI compared to typical SPPS processes. This presentation will further describe ongoing developments for the LPPS process development workflow to make these approaches more accessible at an early stage of clinical development.”

Bio

As Chief Scientific Officer and Site Head, Eric oversees all projects and guides solution delivery by building a deep understanding of all projects through kinetic and thermodynamic analyses. Eric completed his Ph.D. in Organic Chemistry at the University of Toronto under the direction of Professor Mark Lautens. Subsequently, Eric worked with Professor Eric Jacobsen as an NSERC postdoctoral fellow at Harvard University where he focused on asymmetric catalysis and natural product synthesis. He began his industrial career at Amgen in Small Molecule Process and Product Development. He quickly rose in levels of responsibility while developing elegant synthetic routes and brought new process technologies to many complex molecules in Amgen's pipeline. Eric is passionate about the tremendous power and opportunity Snapdragon's core technology brings to the development and application of continuous synthetic routes to complex molecules.

~80% of urinary tract infections (UTIs) are caused by uropathogenic E. coli (UPEC). Adhesion proteins on the pilus-covered surface of UPEC are required for attachment to host cells for colonization and disease progression. The primary adhesion proteins associated with UPEC virulence are FimH and FmlH, which bind D-mannose or D-galactose (respectively) on uroepithelial/kidney cells. Our goal is to develop UTI treatments that prevent the attachment and subsequent internalization of UPEC in host cells, eliminating bacteria from the urinary tract. However, it remains challenging to design long-lived inhibitors that reach the urinary tract without disrupting adhesion in commensal gut bacteria. We are using mirror-image phage display to identify D-peptide inhibitors of UPEC adhesion. Towards this goal, we have synthesized both FimH and FmlH using native chemical ligation of three peptide segments. Both adhesion proteins are densely populated with hydrophobic and negatively charged amino acids, particularly in FimH, making synthesis impractical without the use of removable, solubilizing “Helping Hand” (HH) tags developed by our lab that can be added at Lys or Glu positions. We have developed a folding protocol and confirmed that folded synthetic FimH and FmlH retain the same structure and function, using circular dichroism and sugar binding assays, as their natural counterparts. We are now synthesizing both proteins using D-amino acids to provide D-targets to screen in mirror-image phage display and identify D-peptide inhibitors. These D-peptides will be used to prevent and treat lower and upper UTIs.

Peptide Showcase
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Christa Pawlowski
COO, EVP Research & Development, Haima Therapeutics LLC

Development of Heteromultivalent Peptide-decorated Nanoparticles for Hemorrhage Control

Company Description

Effective hemorrhage control requires rapid platelet activity at the site of injury, yet donor platelets face supply and storage limitations. SynthoPlate is a synthetic nanoparticle decorated with a rationally designed, heteromultivalent set of short peptides that mimic essential platelet functions. These include peptides for binding exposed collagen and von Willebrand factor and binding to endogenous platelets via fibrinogen-mimetic peptides. This modular, peptide-driven design enables site-specific adhesion and amplification of clot formation while minimizing off-target clotting risks. Preclinical studies show that SynthoPlate reduces bleeding time and blood loss with a favorable safety profile. Lyophilization and scalable manufacturing further support its translation as a first-in-class, peptide-based, donor-independent hemostatic therapy.

Bio

Dr. Christa Pawlowski has over 15 years of drug discovery and development experience across therapeutic indications including cardiovascular disorders, inflammatory diseases, immunology, and oncology. Dr. Pawlowski is COO and EVP of R&D at Haima Therapeutics, a company focused on the development of peptide-decorated, platelet-inspired nanotechnologies for the treatment of hemorrhage and other blood-related ailments. She previously served as Director of Operations at BioMotiv, a biotech accelerator, managing two start-ups: SapVax (developing adjuvanted peptide immunotherapies for cancer) and Allinaire Therapeutics (developing biologics for cardiopulmonary diseases). She received her PhD in Biomedical Engineering from Case Western Reserve University.

Peptide Showcase
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Will Van Treuren
Principal Scientist, Aizen Therapeutics

Mirror peptides as a novel therapeutic modality

Company Description

D-amino acids have a long history in peptide and protein medicinal chemistry due to their ability to impart protease resistance. Despite this advantage, developing all-D peptides (mirror peptides) as therapeutics has been infeasible due to a wide range of technical limitations. Aizen is pioneering a AI platform for the design of mirror peptides, marrying the inherent advantages of D-amino acids with in-silico binder design to rapidly develop privileged therapeutic scaffolds. In this talk I'll present an overview of Aizen's computational strategy, and a case study on the design of binders across a range of targets.

Bio

Will Van Treuren holds a PhD from Stanford University (2020). His PhD work focused on microbial metabolism in the human intestine, and the discovery of microbial metabolites with immunomodulatory potential. Will co-founded Interface Biosciences in 2021 based on his PhD work, with the goal of developing endogenous microbial metabolites as immunomodulatory medicines. In 2025, Will left Interface to join Aizen Therapeutics, where he's a Principal Scientist focused on designing and advancing bioavailable mirror peptide programs.

Panel Discussion: Peptides as Radiopharmaceuticals
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Thomas Beale
Senior Director, CMC Early Phase, RLT, Eli Lilly and Company

Peptide Radiopharmaceutical Panel

Abstract

Eli Lilly and Company was incorporated in 1901 in Indiana to succeed to the drug manufacturing business founded in Indianapolis, Indiana, in 1876 by Colonel Eli Lilly. We discover, develop, manufacture, and market products in a single business segment—human pharmaceutical products.

Our purpose is to unite caring with discovery to create medicines that make life better for people around the world. Our long-term success depends on our ability to continually discover or acquire, develop, and commercialize innovative medicines.

We manufacture and distribute our products through facilities in the United States (U.S.), including Puerto Rico, and in Europe and Asia. Our products are sold in approximately 95 countries.

Bio

Thomas (Tom) Beale is currently a Senior Director, CMC Early Phase, RLT at Eli Lilly and Company, with oversight of internal and external precursor development, isotope supply and translational radiochemistry functions to deliver radioligand therapies (RLTs) from candidate identification to clinical studies. He joined Lilly as part of the POINT Biopharma acquisition in 2024, where he was previously responsible for precursor development for early and late stage programs.

Prior to joining POINT, he worked in traditional API development and scale-up as part of Alphora Research (now Eurofins CDMO Alphora) for ~8 years, starting as a bench chemist and eventually having technical leadership of multiple parallel process development programs, from IND-enabling to PPQ and commercial stages with a team of >10 chemists. Overall, he has contributed to >15 IND or equivalent submissions and a number of NDA submissions.

Before starting in industry, Tom completed postdoctoral studies at the University of Toronto in the group of Prof. Mark Taylor, working on methodologies for regioselective glycosylations using boron catalysis with partial support from the Heart and Stroke Foundation. His graduate studies in organic chemistry were performed in the group of Prof. Steve Ley at the University of Cambridge with funding from Cancer Research UK, and his Master's was obtained in Chemistry from Imperial College, London.

Thioamides are valuable peptide bond bio isosteres that offer a powerful means to probe interactions along the peptide backbone. However, their incorporation into peptides, particularly at aspartic acid residues—poses significant synthetic challenges. During solid-phase peptide synthesis (SPPS), thioamides are especially susceptible to Aspartimide formation, a common side reaction that reduces yield and purity. This reactivity complicates elongation steps and often limits access to thioamide-containing sequences using standard synthetic protocols.
In this work, we identify the underlying reasons for this heightened Aspartimide formation and present a strategy to overcome it. We demonstrate that converting thioamides into thioimidates provides an effective and versatile protecting approach during all stages of SPPS. The structural features of thioimidates completely suppress Aspartimide formation, eliminating this major synthetic obstacle. Importantly, this protection strategy is not merely temporary, thioimidates can be selectively transformed after peptide assembly into either amides or amidines. This post-synthetic flexibility allows the generation of both native (unmodified) peptide backbones and backbone-modified analogues from a single precursor synthesized on resin.
A key outcome of this study is the successful and modular installation of amidines at aspartic acid residues, representing a rare application of this underutilized isostere in peptide chemistry. This capability opens new opportunities for tuning hydrogen-bonding networks, modulating conformational stability, and exploring structure function relationships in peptides. Overall, the thioimidate approach addresses a long-standing barrier in thioamide chemistry, enabling efficient synthesis and structural diversification of peptides for biochemical and medicinal studies.

Spotlight on Discovery
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Jung-Mo Ahn
Associate Professor, University of Texas at Dallas

Structure-Based Design of Alpha-Helix Mimetics for Inhibiting Protein-Protein Interactions and Treating Breast Cancer

Abstract

We have designed an oligo-benzamide scaffold as a rigid template to replicate protein helices. It presents side chains of the amino acid residues found at the i, i+4, and i+7 positions in a helix in addition to two substituents at its N- and C-termini for achieving higher affinity, selectivity, and improved physicochemical properties. It has demonstrated outstanding mimicry of LXXLL motifs that is critical to facilitate protein-protein interactions between nuclear receptors and their coactivators. Bis-benzamide D2 was found to disrupt androgen receptor and its coactivators effectively in prostate cancer models, whereas tris-benzamide ERX-11 showed potent inhibition of estrogen receptor in breast cancer models. Recently, our efforts to further improve these leads identified a new therapeutic target, lyososomal acid lipase A (LIPA) for treating hard-to-kill cancers like triple-negative breast cancer. Tris-benzamide-based ERX-41 was found to induce endoplasmic reticulum (ER) stress, resulting in cell death. Mechanistically, ERX-41 binding to LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window with no adverse effects either on normal mammary epithelial cells or in mice. It is also found to be metabolically stable and orally available.

Bio

Jung-Mo Ahn is an Associate Professor in the Department of Chemistry and Biochemistry at the University of Texas at Dallas. He completed postdoctoral research at the Scripps Research Institute after he earned his PhD from the University of Arizona. His research primarily focuses on the development of small molecules to modulate protein function. In particular, he has designed rigid organic scaffold that mimic protein helical surfaces, aiming to disrupt protein-protein interactions. This novel class of molecules has demonstrated an outstanding potential in inhibiting nuclear receptors including androgen and estrogen receptors from interacting with their coactivator proteins. They showed remarkable in vivo efficacy in inhibiting the growth of prostate and breast cancer cells. He has authored over 100 peer-reviewed publications and holds multiple patents.