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Small Molecule Drug Conjugates
Small Molecule Drug Conjugates

Small Molecule Drug Conjugates (SMDC)

Bio-Synthesis offers small molecule conjugation and modification by covalently attaching drugs, metabolites and labeled compounds with synthetic or natural polymers for specific applications. Conjugation of these high affinity small molecules with biopolymers provide a variety of biological functions such as cell signaling molecules, as tools in molecular biology, as drugs in medicine, and in many other roles. Our experience in small molecule synthesis, modification and conjugation includes but not limited to:

  • Small molecule - nanoparticle conjugation for cell-specific targeting
  • Modification of peptide, oligonucleotide and protein with small molecule - thioester, NHS ester
  • Small molecule (cancer drug) to antibody for therapeutic study
  • Small molecule immobilization for affinity purification
  • Modification of oligonucleotide, peptides, protein with small molecule for Epigenetic Research
  • Preparation of protein tags: ubiquitin, SUMO and related modifiers for DNA repair, autophagy and signal transduction studies
  • Small molecule: Adrenergic agonist, mycotoxins, antibiotics, steroid hormones can be conjugated with a carrier protein for antibody production and agarose for affinity purification.
  • Oligoribonucleotide−ligand conjugates using the copper-catalyzed azide−alkyne cycloaddition (CuAAC) or click reaction.
  • Small Molecule Ligand -Drug Conjugates for Targeted Cancer Therapy

Our highly skilled chemists can carry out the synthesis of various complex intermediates, scaffold, reference compounds and a wide range of research building blocks. All custom small molecule synthesis and conjugation complexes are manufactured under a strict quality control throughout the entire production cycles to minimize variations and ensure superior QUALITY, higher RELIABILITY, and CONSISTENCY in our products. At Bio-Synthesis, we strive with competence and confidence to meet your demand for developing pre-clinical drug candidates or innovative regents and tools efficiently and affordably. With our track record, Bio-Synthesis is your ideal and reliable innovation partner in targeted drug discovery.

Biomolecules such as oligos and their analogs, peptide, peptidomimetics, antibody fragments, enzymes, and other user-supplied biomolecules that have a functional group can be used for conjugation. These biomolecules can be modified and linked to one or several small molecules through homobifunctional or heterobifunctional linkers via selective or non-selective covalent bond. Since choosing the correct chemistry can sometimes seem overwhelming, it requires a careful understanding of target molecule's structure and reactivity. These cross-linking and modifying agents can be applied to alter the native state and function of peptides and protein; sugars and polysaccharides; nucleic acids and oligonucleotides; lipids; and almost any other imaginable molecule that can be chemically derivatized. Each conjugation project assigned to Bio-Synthesis is carefully designed, modified and strategized. Bio-Synthesis not only offers synthesis of biopolymers, but also assists clients who want to functionalize or activate compounds ready to cross-link with pre-activated biomolecules, either supplied by customers or prepared in-house. These pre-activated small molecules can be created with an amine, acid, hydrazine, aldehyde/ketone, hydromxyamine, maleimide/alkylhalide, and sulfhydryl functional group in a polymer. After conjugation of a biopolymer with other biopolymers, a standard desalting, purification, quality check and final concentration and labeling ratio are determined.

Sample Requirements

Non-commercial small molecule supplied by customer

User-supplied, non-commercial small or macromolecules should be sufficiently pure (≥95% pure). Please provide the QC data (typically HPLC, MS, ESI or NMR data etc.) and MSDS (if any) along with your compound. We can assist with the purification and acquisition of analytical data. These compounds must contain functional groups that can be targeted for cross-linking including carboxylate groups, primary amine groups, aldehyde/keto residues, hydroxyl, hydrazine, hydrazide, aminoxy, saccharide /glycan groups or thiol reactive functional group(s). Coupling also can be nonselective using a photoreactive phenyl azide cross inker. If necessary, we can also assist with the creation and activation of specific functionalities. Any sample supplied by the client requires a quality check by our analytical team to ensure sample quality prior conjugation.

Commercial available small molecules

Commercially available small molecules can be supplied by customers or ordered through Bio-Synthesis. Common small molecules such as common fluorescent dyes, biotin-NHS and other hetero-bifunctional cross-linkers are available at Bio-Synthesis. For in stock compounds, Bio-Synthesis will charge customers only the amount needed for conjugation. If the small molecules are to be purchased separately, the cost of acquiring this material will be added to the invoice along with a $50 administration charge per order.

Non-commercially available small molecules

We can custom synthesize small molecules either in house. A quotation will be prepared for such syntheses.

Oligonucleotide, oligomimetics and custom gene or genomic DNA

DNA, RNA and nucleic acid analogs such as PNA can be synthesized in-house at Bio-Synthesis, and then conjugated through amino, thiol, aldehyde, azide, carobxyl or 5'-phosphate modification. Oligos supplied by the customer should be HPLC or gel purified (>90% pure). Please provide the QC data needed for purity assessment. Extra charges may apply for analyzing the starting materials at Bio-Synthesis.

Peptides, peptidomimetics, and expressed protein

Peptides or proteins can be synthesized or expressed in-house at Bio-Synthesis. We label or conjugate peptides through N-terminal, C-terminal or internal side chain of amino acids. Peptides supplied by the customer should be HPLC purified (>90% pure) and should contain a single modification site. We can make any standard peptide with functional groups incorporated through peptide synthesis. Please provide the peptide sequence of the desired peptide on the order form.

Antibodies

Commercial antibodies can be supplied by customers or ordered through Bio-Synthesis with an additional fee plus the cost of the antibody. Non-commercial biopolymers supplied by customers should be affinity purified. Please provide gel electrophoresis data along with your antibody. Bio-Synthesis also assists customers with antibody production, purification, modification, fragmentation prior to any cross linking reaction.

Functional target modification services

We offer post-synthetic modification of ligands to be immobilized on various solid supports, which allow the immobilization process to occur selectively in the presence of common functional groups, including amines, thiols, carboxylic acids, and alcohols. Bio-Synthesis offer functional group modification and deravitization;

  • Amino acid, peptides and protein modification
  • Modification of sugars, polysaccharides and glycoconjugates
  • Modification of nucleic acids and oligonucleotides
  • Creating Specific functionalities such as sulfhydryl, carboxylate, primary amine, aldehyde/ketone, hydrazine or hydrazide, saccharide or glycan groups
  • Blocking functional group such as amine, sulfhydryl, aldehyde or carboxylate group.

See more information on Biomolecule Modification

Chemistry of Reactive Group used

Every chemical modification or conjugation process involves the reaction of one functional group with another, resulting in the formation of a covalent bond. The creation of bioconjugate reagents with spontaneously reactive, or selectively reactive functional groups, forms the basis for simple and reproducible cross-linking or tagging of target molecules. Our well-trained chemists assist clients from starting project scope collections to design, and determine appropriate homobiofunctional or heterobifunctional cross-linking chemistries. We have delivered thousands of custom conjugated biopolymers and are fully capable of meeting the ever-increasing bioconjugation needs in biological and drug discovery research. Hundreds of reaction systems have applied in our organic laboratories.

  • Amine Reaction: NHS ester, imidoester, hydroxymethyl phosphine, Guanidination of amine, fluorophenyl esters, carbodiimides, anhydrides, arylating agents, carbonates, aldehydes and glyoxals
  • Thiol Reactions: Maleimide, Haloacetyl, Pyridyldisulfide, Vinyl sulfone, Thiol-disulfide exchange
  • Carboxylate reactions: Carbodiimides
  • Hydroxyl Reactions: Isocyantes, enzymatic oxidation, Carbonyldiimidazole
  • Aldehyde and Ketone Reaction: Hydrazine derivative Schiff Base formation, reductive amination
  • Active Hydrogen Reaction: Iodination reaction
  • Photo-chemical Reactions: Psoralen compounds, aryl azides and halogenated aryl azides, bensophenones, anthraquinones
  • Cycloaddition Reaction: Chemoselective ligation such as Click chemistry, diels-alder reaction
  • Contract Research Development

Small Molecule Biopolymer Conjugation Service Description

Price:

Price varies based on the project specifications. Price does not include the cost of small molecule or biopolymer which is required to be supplied by the customer or ordered through Bio-Synthesis from a commercial vendor. Some of the small molecules are commercially available in an activated form. For non-active molecules, Bio-Synthesis can assist with the design and, if deemed necessary, biopolymer modification to introduce additional functional groups and extra linkers. Please contact us for a quote.

Chemistry:

Using preactivated small molecule and biomolecule with chemical reactive groups such as amine, thiol, carboxylate, hydroxyl, aldehyde and ketone, active hydrogen, photo-chemial and cycloadition reactions and cross link via zero-length , homobifunctional, heterobiofunctional or multi-functional cross-linking chemistries, denrimer and dendrons, cleavable regent system.

Service Specification:

After standard desalting, or purification, a small percent of heterogeneous products containing single or multi-site conjugate per molecule may exist.

Procedure:

All custom synthesis of biopolymer, modification or bioconjugation of small molecule services are manufactured under strict quality control processes. Analytical HPLC and MS analyses are performed in every development cycle. Final target conjugates must first be isolated from excess or unreacted reagent. In many cases, simple dialysis may suffice to remove unreacted reagent from the reaction solution. Depending on the project scope, size-exclusion chromatography (SEC), HPLC, may also be used to either remove excess reagent or isolate and characterized the cross-linked product. Cross-linked target molecules may then be further characterized by biochemical or biophysical techniques. Once the product has been purified, it may be subject to many different types of studies including spectroscopic (MALDI-top, ESI, LC-MS Fluorescence), electrophoresis, immunochemical biochemical, enzymatical analysis. QC (quality control) and QA (quality assurance) procedures are also followed independently to offer you double guarantee for the highest quality possible of every delivered conjugates. Moreover, our dedicated technical account managers will guide your project through every step of the process and constantly keep you informed of the latest project progress.

Delivery Specifications:

The typical delivery consisted of lyophilized sample in individual fully labeled vials, shipment also contain COA, MS, HPLC and/or other analytical data. Additional analytical data also available upon request.


Bioconjugation Service Questionnaire


Reference/Citing:

  1. Upadhyay, A. et al.: Immunological Response to Peptide Nucleic Acid and its Peptide Conjugate Targeted to Transactivation Response (TAR) Region of HIV-1 RNA Genome; Oligonucleotides. 18(4) 2008.
  2. Olejnik, J. et al.: Photocleavable peptide-DNA conjugates: synthesis and applications to DNA analysis using MALDI-MS; Nucleic Acid Researech. 27 (23) 1999.
  3. Pai, S. et al.: Proximity ligation assays with peptide conjugate 'burrs' for the sensitive detection of spores; Nucleic Acid Research. 33(18) 2005.

Visit our literature vaults for more references and citings.

Ordering and Submitting Requests for Bioconjugation Services

For us to better understand your customized project, please complete our Bioconjugation Service Questionnaire. The more our chemists understand your project needs, the more accurate feedback we will be able to provide you.  Provide us with your project details will enable to us to recommend the best reagents to use for your project.  The most useful and readily available tools for bioconjugation projects are cross-linking reagents. A large number of cross-linkers, also known as bifunctional reagents, have been developed.  There are several ways to classify the cross-linkers, such as the type of reactive group, hydrophobicity or hydrophilicity, and the length of the spacer between reactive groups.  Other factors to consider are whether the two reactive groups are the same or different (for example, heterobifunctional or homobifunctional reagents), whether the spacer is cleavable, and whether the reagents are membrane permeable or impermeable.  The most accessible and abundant reactive groups in proteins are the ϵ-amino groups of lysine.  Therefore, a large number of the most common cross-linkers are amino selective reagents, such as imidoesters, sulfo-N-hydroxysuccinimide esters, and N-hydroxysuccinimide esters.  Due to the high reactivity of the thiol group with N-ethylmaleimide, iodoacetate and a-halocarbonyl compounds, new cross-linkers have been developed that contain maleimide and a-carbonyl moieties.  Usually, N-alkylmaleimides aremore stable than their N-aryl counterparts.

In addition to the reactive groups on the cross-linkers, a wide variety of connectors and spacer arms have also been developed.  The nature and length of the spacer arm play an important role in the functionality.  Longer spacer arms are generally more effective when coupling large proteins or those with sterically protected reactive side-chains.  Other important considerations are the hydrophobicity, hydrophilicity, and the conformational flexibility.  Long aliphatic chains generally fold on themselves when in an aqueous environment, which makes the actual distance spanned by such linker arms less than expected.  Instead, spacers that contain more rigid structures (for example, aromatic groups or cycloalkanes) should be used.  These structures, however, tend to be very hydrophobic which could significantly decrease the solubility of the modified molecules or even modify some of their properties.  In such cases, it is recommended to choose a spacer that contains an alkylether (PEO) chain.  Bio-Synthesis offers several cross-linkers with PEO chains, such as thiol-binding homobifunctional reagents, heterobifunctional based, and their derivatives.

Within 3-5 days upon receiving your project scope, we will provide you an appropriate quotation. An order can be placed with PO (Purchase Order) or major credit cards ( ). Your credit card will be billed under Bio-Synthesis, Inc.