Peptide Conjugates

1.peptide drug conjugates

Ⅰ. introduction

Peptides are emerging as a promising class of targeted cancer drugs. As short chains of amino acids, peptides can be designed to bind specifically to proteins found predominantly on cancer cell surfaces. Conjugating these cell-targeting peptides to chemotherapy agents allows for selective delivery of potent cytotoxins to tumor tissues. The resulting peptide drug conjugates (PDCs) offer an innovative approach to treating cancers while minimizing unwanted side effects.

PDCs represent a new generation of antibody-drug conjugates (ADCs) - an established category of targeted cancer therapy. While ADCs utilize full-size antibodies for cell targeting, PDCs employ much smaller peptides. This change provides key advantages like enhanced tumor penetration, rapid clearance, and lower immunogenic risk. At the same time, peptides are large enough to achieve necessary specificity for cancer biomarkers.

Development of PDCs builds on decades of advances in cancer biology and medicinal chemistry. Personalized medicine has revealed how genetic mutations and protein expression patterns enable tumor cells to proliferate uncontrollably. And high-throughput sequencing has elucidated the distinctive landscapes of receptors and signaling pathways driving different cancers. Now, the vision is to exploit these differences with tailored peptide targeting sequences.

Modern linker chemistries also make it possible to connect those targeting peptides with extremely potent drugs. Some PDCs utilize traditional chemotherapeutics like doxorubicin. But the primary goal is to overcome multidrug resistance by using highly cytotoxic agents too hazardous for standard systemic administration - including auristatins, maytansines, and duocarmycins. Conjugation technology transforms these substances into safe, selective weapons for eradicating cancer.

In summary, PDCs merge the specificity of cancer biology with the potency of next-generation cytotoxins. The latest research demonstrates that peptide conjugates can selectively destroy tumor cells while reducing side effects. Our company is at the leading edge for translating these innovative PDCs into viable clinical therapies. Please reach out to learn more about our capabilities.

The structures of bicycle-toxin conjugates BT5528, BT8009 and BT1718 developed by Bicycle Therapeutics. * Image from "Peptides as a platform for targeted therapeutics for cancer: Peptide–drug conjugates (PDCs)." Chemical society reviews 50.3 (2021): 1480-1494.

Ⅱ. What We Can Do

Peptides: Custom Design and Synthesis for Targeted Delivery

As a core PDC component, the targeting peptide determines selectivity for cancer cells overexpressing a particular protein. We leverage computational modeling and structure-activity-relationship data to custom design peptides with:

• High binding affinity and specificity
• Rapid tumor penetration and retention
• Tunable pharmacokinetic properties like circulation half-life                                                                                                         

Our chemists have successfully synthesized diverse cancer-targeting peptides including:

• RGD peptides that bind integrins overexpressed in tumors
• Glypican-3 targeting peptides for hepatocellular carcinoma
• Peptides targeting VEGF, HER2, EGFR and other cancer biomarkers                                                                                              

We utilize Solid Phase Peptide Synthesis with Fmoc chemistries to manufacture gram quantities of >98% pure peptide. Our responsive supply chain ensures access to necessary protected amino acids and resins.

Linkers: Customizable Connection to Optimize Stability and Release

The linker connects the targeting peptide to the cytotoxic drug, balancing PDC stability in circulation versus efficient drug release inside cancer cells. We leverage various linker chemistries to attach payloads at the C- or N-terminus or via lysine side chains. Different linkers provide:

• Tunable biochemical properties (e.g. pH-sensitive)
• Variable serum stability and drug release rates
• Strategies for overcoming drug resistance                                                                                                                                 

Payloads: Most Potent Cytotoxins for Overcoming Chemoresistance

We offer conjugation to diverse cytotoxin payloads for disrupting essential cell processes like microtubule polymerization and DNA synthesis. Payloads range from classic chemo drugs to emerging topoisomerase and tubulin inhibitors designed to defeat treatment resistance. Utilizing appropriate spacer-equipped derivatives, we attach payloads like:

Auristatins (MMAE, MMAF)

Maytansines (DM1, DM4)

Duocarmycins (DC)

Doxorubicin

Camptothecins

2. peptide oligonucleotide conjugates

Ⅰ. introduction

Gene therapy holds enormous promise for treating diseases at their genetic root cause. However, effectively delivering oligonucleotide-based therapies like siRNAs, antisense oligos, and CRISPR components into target cells in a specific and safe manner remains a major challenge.

peptide oligonucleotide conjugates. *Image from "Emerging applications of peptide–oligonucleotide conjugates: Bioactive scaffolds, self-assembling systems, and hybrid nanomaterials." Organic & biomolecular chemistry 17.7 (2019): 1668-1682.

Peptide-oligonucleotide conjugates (POCS) have recently emerged as a leading platform to overcome this delivery challenge through the synergistic fusion of two key components:

Oligonucleotide Cargo: This genetic payload (DNA, RNA, or analogues) provides sequence-based specificity to target and alter expression of practically any gene of interest. Common examples include:

• siRNAs/shRNAs for knockdown via RNA interference
• Antisense oligos for degradation of target mRNAs
• CRISPR guides to direct genomic editing                                                                                                                                 
• ssDNAs labeled with fluorophores as hybridization probes

Cell-Penetrating Peptides: These are short (5-25 aa), cationic peptides with intrinsic ability to transport conjugated cargoes across cell membranes efficiently via endocytosis. By undergoing conformational changes or forming transient pores, they enable endosomal escape into cytoplasm. Connected via a flexible linker, the oligonucleotide cargo leverages the cell penetration capacity of the peptide to achieve robust intracellular delivery. Recently developed biorthogonal conjugation strategies also allow synthesis of POCs with precisely defined components at a large scale.

Extensive preclinical data has now demonstrated POCs yield enhanced stability, circulation half-life, cellular uptake, and gene silencing abilities compared to naked oligonucleotide approaches. Our company brings state-of-the-art expertise in POC design, optimization, and manufacturing to convert theoretical promise into clinical realities.

Ⅱ. Our POC Platform Offers Custom Design and Production

As leaders in POC technology, our company provides start-to-finish development capabilities including:

• Rational design of cell penetrating peptides
• Custom oligonucleotide synthesis (DNA, RNA, LNAs)
• Biorthogonal conjugation strategies                                                                                                                                 
• Flexible linker design for optimized pharmacokinetics
• Purification, characterization and quality control

Whether you need an established reagent scaled-up or have an idea for an entirely novel POC architecture, our scientific team has the expertise to make it happen.

3. peptide phospholipid conjugates

Ⅰ. introduction

For decades, liposomes have shown promise as biocompatible carriers of life-saving therapeutics - enabling enhanced drug solubility, higher tumor accumulation through EPR effect, and reduced system toxicity. However, multiple barriers including poor cellular uptake and rapid clearance have prevented their full potential. Recent advances in peptide-phospholipid conjugation provide solutions through targeted delivery.

Schematic illustration of liposome-encapsulated therapies. (Left) FDA-approved therapies for chemotherapeutic-encapsulated liposomes (top left) without PEGylation and (bottom left) with PEGylation. (Right) Peptide-functionalized liposomes for receptor-targeted chemotherapeutic delivery. *Image from "Peptide functionalized liposomes for receptor targeted cancer therapy." APL bioengineering 5.1 (2021).

Liposomes contain spherical phospholipid bilayers with aqueous cores. Common constituents include phospholipids like DSPC, DSPE-PEG2000, and cholesterol to provide stability and circulation time. Hundreds of research publications and dozens of approved products highlight utility of liposomes for encapsulating small molecule drugs, protein therapeutics, gene therapies and imaging agents. While substantial progress, enhancing intracellular liposomal delivery for optimal therapeutic index remains an elusive goal.

By covalently attaching specialized targeting peptides to the liposome surface, our pioneering peptide-phospholipid conjugation technology enables high-affinity binding to overexpressed cell receptors. This promotes cellular uptake through endocytosis - thereby enhancing drug delivery, effective dosing and therapeutic outcomes for oncology, genetic and infectious diseases.

Ⅱ. What We Can Do

As pioneers in actively targeted liposomal carriers, a core specialization of our company is efficient, scalable synthesis of peptide-phospholipid conjugates.

These innovative conjugates fuse the targeting specificity of peptides with the self-assembly and drug encapsulation properties of phospholipids. Incorporating the resulting constructs into liposomal formulations presents cell-specific peptide ligands on the outer surface for preferential binding to desired cell types. This enhances selective intracellular uptake compared to passively targeted regular liposomes lacking peptide guidance capabilities.

Over years, we have honed an exemplary competence in developing and producing diverse peptide-phospholipid conjugates including:

• Proprietary chemo-selective ligation techniques enabling high-yield, irreversible peptide-lipid coupling under mild aqueous conditions
• Solid phase peptide synthesis expertise - Fmoc chemistries - for producing tailor-made targeting ligands
• Diverse in-house library of phospholipid derivatives for conjugation including DSPE-PEG-maleimide, DSPE-PEG-alkyne and novel structures                                                                   
• Quality control analytics leveraging LC-MS and HPLC equipment
• Scalable process suite supporting high purity >100g GMP scale conjugate supply

Whether early proof-of concept explorations or technology transfers for late-stage clinical manufacturing, our end-to-end capabilities can advance peptide-functionalized liposomes from idea to therapeutic reality.

The below list highlights just a sample of the phospholipid derivatives we can leverage for efficient biorthogonal conjugation with targeting peptides of interest.

Additionally, our specialized expertise in lipid chemistry and custom process development enables synthesis of novel peptide-phospholipid conjugates using your preferred phospholipid substrates - whether commercially available structures or custom entities designed in-house to meet specific requirements.

Name	Structure
DSPE-PEG-Maleimide
DSPE-PEG-NH2
DSPE-PEG-NHS
DSPE-PEG-COOH
DSPE-PEG-SH