Main Conference - Day 2 (May 13)Wednesday, 13 May 2026

Oligonucleotide therapeutics (ONTs) are poised to become the third pillar of modern medicine. However, the practical and large-scale synthesis of ONTs and their constituent nucleoside analogue (NA) building blocks remains a major challenge. As each of the NA units must be individually designed and tailored to enhance the desired ADMET properties of the ONT, identifying economic, flexible, and scalable syntheses of these compounds is of critical importance. To date, the field has relied almost exclusively on carbohydrates as starting materials for NA synthesis. While these compounds are enantiopure and share common structural and stereochemical features with NAs, their conversion into NAs often requires long, challenging, low-yielding and expensive synthetic campaigns. As a result, a large fraction of ONT chemical space remains unexplored and the full impact of chemical modification on the pharmacokinetic properties of ONTs remains poorly understood. Here, we present a streamlined platform to produce NAs that should improve access to precision edited ONTs. This approach uses achiral starting materials and relies on a dual organocatalyst, one-pot process to furnish a key class of ONT building blocks: the RAvIN ketones (RKs). Notably, RKs can incorporate appropriately protected natural nucleobases as well as nucleobase analogues, be made on scale in 2-4 steps with carbohydrate-like levels of enantiomeric purity and are readily diversified to create the next generation NAs required to improve physiochemical properties of ONTs. Finally, we demonstrate the versatility and potential of this methodology in a total synthesis of the all-MOE-modified RNA 18mer nursinersen.

Enzymatic methods are transforming oligonucleotide synthesis by offering higher precision, milder conditions, and greater sustainability compared to traditional chemical approaches. A key step in this process is the efficient production of 5′-NTP building blocks, where enzymatic routes provide clear advantages over chemical synthesis, such as better selectivity, higher yields, and simpler workflows. Here we showcase powerful enzymatic strategies for efficient 5′-NTP synthesis, leveraging purified enzymes with nucleobases or nucleosides as starting materials. These approaches unlock new possibilities through integrated ATP regeneration systems that drive efficiency and sustainability. By highlighting the transformative potential of in vitro enzymatic cascade reactions, we emphasize their value as cutting-edge tools with broad impact across basic research and industrial applications.

The growing demand for therapeutic oligonucleotides requires new, efficient, scalable, and sustainable manufacturing solutions. This presentation will showcase Codexis’ ECO Synthesis® Manufacturing Platform, an enzymatic process for producing high-quality siRNA that operates under fully aqueous conditions, eliminating the need for highly reactive chemicals and dramatically decreasing acetonitrile use.

This talk will introduce XtalPi's PepiX™, a leading AI peptide R&D platform. It integrates AI design, automated synthesis, and high-throughput screening, enabling efficient "design-synthesis-verification" cycles. PepiX™ unlocks the design and discovery of peptide drugs by vastly expanding chemical space searching via proprietary noncanonical amino acids. Case studies include a tumor vaccine candidate with strong preclinical results, solving challenges of an undruggable target, an oral weight-loss peptide development, and also efficient BBB penetration and delivery using peptides. PepiX™ sets a smart and efficient peptide R&D benchmark.

The explosion of chemical building-blocks for peptides creates a conundrum: from astronomical numbers of combinatorial possibilities, what sequences should we synthesize? This presentation covers the state-of-the-art computational pipeline for rational peptide design using the Rosetta software suite, as well as ongoing pipeline enhancements being implemented in the Masala software suite.

Traditional solid-phase oligonucleotide manufacturing faces inherent limitations that may restrict the broader application of synthetic oligonucleotide therapeutics, particularly in prevalent disease areas. To address these challenges, we have been developing a next-generation, hybrid manufacturing platform that integrates solid-phase synthesis of short blockmers and solution-phase, enzyme-mediated ligation reaction. This hybrid approach offers a promising path toward scalable, efficient, sustainable and high-quality production of therapeutic oligonucleotides. Alnylam’s progress in this approach will be presented.

The chemistry of oligonucleotide is getting increasingly complex with additions of modification that aim to improve their overall efficacy or biodistribution. The Mesylphosphoramidate is a chemical modification that requires the use of mesylazide, a potentially explosive reagent. This presentation describes how mesylazide was introduced at Biogen and its various risks mitigated.

The rapidly growing number of therapies approved and in advanced clinical trials is placing unprecedented demands on our capacity to manufacture oligonucleotides at scale. This talk will describe several complementary biocatalytic approaches to efficiently produce oligonucleotides in a more sustainable fashion.

We introduce BoltzGen, an all-atom generative model for designing proteins and peptides across
all modalities to bind a wide range of biomolecular targets. We experimentally validate its capabilities in a total of eight diverse wetlab design campaigns with functional and affinity readouts across 26 targets.

This presentation will discuss the analytical challenges associated with characterizing the diastereomer composition of oligonucleotide therapeutics and explore advancements in both analytical and statistical methods to overcome these limitations. The focus will be on the use of specific examples involving FDA-approved drugs and synthetic analogues to demonstrate the value of integrating analytical methods with validated statistics.

I will present key multidisciplinary scientific milestones that have led to fifty years of melanocortin receptor (MCR) targeted peptide drug discovery as well as several recent FDA approvals. Knowledge of key MCR targets (e.g., MC1R, MC3R and MC4R) has significantly advanced in recent years in terms of structural biology and pharmacology. Likewise, the design of MCR targeted peptides having improved drug-like properties will advance the next generation of breakthrough medicines.

Oral peptide antagonists targeting the IL-23/IL-17 axis represent a promising new class for immune-mediated diseases. PN-881, a first-in-class and potential best-in-class oral IL-17 antagonist peptide, demonstrated potent and selective inhibition across IL-17AA, AF, and FF dimers. Preclinical studies demonstrate robust target engagement, excellent metabolic stability, and strong efficacy in inflammation models. These results highlight the potential of Protagonist Therapeutics’ peptide platform to deliver orally bioavailable, highly selective immune modulators and position PN-881 as a leading candidate in advancing peptide-based therapies for inflammatory diseases.

We describe a targeted lipid nanoparticle platform enabling in vivo generation of transient CAR T cells to achieve rapid, B cell depletion without lymphodepletion. In non-human primates, delivery of anti-CD20 CAR mRNA resulted in CAR expression on CD8+ T cells and induced profound B cell depletion in blood and lymphoid tissues including spleen, bone marrow and lymph nodes. Demonstrating an excellent safety and tolerability in NHPs, this off-the-shelf candidate allows B cells recovery to occur with predominantly naïve phenotypes, supporting immune reset and translational potential for autoimmune diseases.

Helically constrained (Helicon) peptides enable the engagement, inhibition, and degradation of intracellular target proteins that are intractable to other therapeutic modalities. This talk will present the platforms that Parabilis has developed to explore the vast chemical space that Helicons can access, and will describe the hit discovery screen used to develop FOG-001, a clinically active β-catenin/TCF inhibitor that is currently in Phase 1/2 clinical trials.

Peptide radioconjugates are a relatively new generation of oncology treatment, combining small format tumour-targeting with precision delivery of radiation. Among the many advantages of peptide radioconjugates such as high target specificity, rapid clearance, modularity, minimal immunogenicity and ease of manufacture, there are numerous physiological challenges to overcome. Within this talk I would like to discuss emerging strategies to address such challenges arising during the development of peptide radioconjugates.

The presentation will discuss the discovery journey of ²²⁵Ac-ETN029, a macrocyclic peptide-based radioligand therapy intended for SCLC and other DLL3-expressing tumors. Structure-based drug design to enhance potency and optimize in vivo biodistribution will be discussed. Additionally, the efficacy study in DLL3-expressing xenograft models will be presented to highlight robust tumor regression. These studies support further investigation of the novel therapeutic ²²⁵Ac-ETN029 as a treatment for patients with DLL3-expressing solid tumors.