What are synthetic biomolecules?

Biomolecules are the building blocks of the living system present at the molecular level - carbohydrates, proteins, and lipids. Synthetic biomolecules are the amalgamation of the physical and chemical aspects of biomolecules, 1 which can be used in various biological platforms, which require a broad range of applications. 2

Need for synthetic biomolecules

Synthetic analogues of biomolecules can be used as antimicrobial agents, as well as possessing pharmacological applications. Synthetic equivalents of naturally occurring biomolecules can be constructed to function in a manner more potent as compared to the naturally occurring biomolecule. 3

Synthetic Carbohydrates

Carbohydrates are extremely versatile molecules owing to the basic constituent carbon skeleton, which lends diversity in terms of orientation, structure, and constitution. The replacement of even a single constituent atom in this carbon skeleton results in the formation of a uniquely distinct molecule. Additionally, carbohydrates possess the property of combining with non-carbohydrate molecules, resulting in the formation of glycoproteins, glycoproteins, etc. 4

The significance of synthetic carbohydrates can be seen in the fields of drugs, drug delivery, vaccines, as well as adjuvants. 5

Carbohydrate-based drugs – Glycomimetics is the class of drugs which is derived as a result of protein-carbohydrate interactions. These drugs possess the activity of carbohydrates in living cells, whilst making up for the drawbacks of carbohydrates possessing insufficient pharmacological properties. 6 For example – Miglustat is a synthetic analogue of D-glucose, and is used for the treatment of Type 1 Gaucher’s disease (a disorder of carbohydrate metabolism caused by the deficiency of the enzyme Glucocerebrosidase). 7

Carbohydrate-based drug-delivery – Delivery systems can be used for delivery of antigens, macromolecular drugs, etc. Lectins present as cell-surface receptors can serve as the binding site for carbohydrates. 8 Boronate containing co-polymers (BCCs) are water soluble which makes them extremely suitable for drug delivery, as well as preparing materials which are responsive to glucose. Additionally, BCCs possess multivalence for carbohydrates which is highly flexible as well as reversible. This property enables cell adhesion to BCC surfaces. 9

Carbohydrate vaccines – It has been found that microorganisms and pathogens possess a wide range of epitopes which are glycan in chemistry. Carbohydrates can be used as vaccines as glycan epitopes found on the surface of pathogens display immense diversity and uniqueness, and are densely distributed on the pathogenic surface. 10 Synthetic carbohydrates require a proper introduction in the patient with a suitable construct. The antibodies generated against these synthetic antigens can be used to destroy those tumour cells which display receptors for these antigens. Different kinds of synthetic carbohydrate vaccines can be used for immunization purposes – (1) Monomeric vaccines, (2) Monomeric clustered vaccines, (3) Unimolecular multi-antigenic vaccines, (4) Dual acting vaccines. 11

Carbohydrate adjuvants – Carbohydrates are easily tolerated by the immune system and do not display adverse effects compared to other immunological agents. They are metabolized easily, and possess very little risk of metabolic toxin generation. When Hepatitis B surface antigen is administered in the form of a vaccine alongwith beta-glu6 as the adjuvant (synthetic analogue of lentinan polysaccharide), it has been observed that the B-cell and T-cell immune response is heightened, alongwith increased chemotactic activity displayed by macrophages. If HBsAg is introduced in the form of a DNA vaccine, beta-glu6 enhances the response of the CD8 cells which are specific to the antigens present. 12

Synthetic dietary carbohydrates – Two carbohydrates have been synthetically produced for dietary purposes – Polydextrose and Neosugar. 13

· Polydextrose – This is a synthetic polymer of glucose (dextrose) in combination with sorbitol and citric acid (all natural ingredients but synthetically produced). It is regarded as soluble fibre by the Food and Drug Administration (FDA). Polydextrose can be used to replace sugar in beverages, candies, puddings, etc. It has low calorific value (1 kCal per gram), and has been shown to display beneficial prebiotic effects. However, intolerance towards polydextrose has been reported in manner much more severe as compared to psyllium husk. 14

· Neosugar – This is a synthetically-derived short chain fructooligosaccharide, which is believed to exhibit beneficial effects on the intestinal microflora. 15 Neosugar is derived from genetically-modified sugar cane or sugar beets, and the processing agent is Aspergillus japonicas. On a commercial scale, the production of Neosugar also involves the presence of synthetic substances such as hydrochloric acid, sodium hydroxide, and active carbon. 16

Synthetic Proteins

Synthetic proteins are also known as Peptoids. 19 These are molecules which possess the ability to mimic the action and properties of naturally occurring proteins. 17

Naturally occurring proteins are coded for by DNA through the processes of transcription and translation. Thus it can be stated that synthetic proteins are coded for by those genes which are not found in nature. If living matter can indeed be sustained through such synthetic molecules, it means that the constituent cellular components and molecules are not limited to natural sources alone. 17

The properties of synthetic proteins need to be identical to naturally occurring proteins, such as stability, folding, hydrophobic core, etc. 17

Peptoids are less vulnerable to enzymatic or chemical lysis as compared to naturally occurring proteins. 19 They are significant in the following areas –

Enzyme Catalysis - Existing protein molecules can be subjected to recombinant techniques or modification by chemical agents in order to convert a naturally-sourced enzyme into an artificial enzyme of proteinic origin. For instance, subtilisin is a protease enzyme isolated from the microorganism Bacillus subtilis. Subtilisin is subjected to chemical modificiation by substituting the serine group with a selenocysteine. This resultant product is a synthetic proteinic enzyme known as Selenosubtilisin. This synthetic enzyme can be applied in the field of protein synthesis due to its ligase action and lack of peptide hydrolysis. 18

Pharmaceuticals – Peptoids mimic the bioactivity of protein molecules and can even be used as therapeutics, replacing smaller molecules. 41 Polyguanidine peptoids which are fluorescently labeled are known as Trojan peptoids as they can rapidly enter plant cells (Tobacco BY-2) for delivery of bioactive substances, whilst not disrupting the cellular viability of these plant cells. 42

Material Science – Peptoid Polymers can be synthesized to a chain of 50 monomers or bulkier polymeric sequences, which can be used in nanoscience and biomedicine. 43

Synthetic Lipids

The main examples of lipid molecules which possess synthetic analogues are cholesterol, triglycerides, glycerol, fatty acids, and lipidemic compounds.

Cholesterol analogue – Cholesterol tagged with fluorescent boron dipyrromethene difluoride (BODIPY-cholesterol) can be used as a probe for analysis and monitoring of sterols in cells of living organisms. 31 Cholestatrienol is a synthetic compound which displays fluorescence properties. This can be used for analysis of cholesterol transportation inside cells as well as cell-to-cell transportation. 32

Triglyceride analogue – Polyiodinated triglyceride (ITG) is a synthetic compound that possesses glycerol as its core. 33 CT signals can thus be attenuated owing to the presence of iodine and its corresponding residues. 34 The triglyceride origin results in the compound being used for deliverance of lipophilic emulsions in hepatocytes as well as reconstitution of molecules that transport low-density lipoproteins. 33 Caprylic acid triglyceride is a synthetic triglyceride used in skin care formulations. It is saturated and is resistant to oxidation. 38

Glycerol analogue – Synthetic Monomycolyl Glycerol (MMG) is a 32-carbon containing compound and possesses the ability to stimulate dendritic cells of the immune system, and enhance the production of cytokines. This can be used as an adjuvant in vaccines against tuberculosis so as to stimulate immune response. 35,36

Fatty acid analogues – 2-hydroxy oleic acid is a synthetic analogue of oleic acid (a monounsaturated fatty acid). It possesses anti-tumour activity. 37

Analogues of lipidemic compunds – N-cholesteryl sphingomyelin is a synthetic sphingolipid that exhibits properties such as exhibiting cholesterol-like behavior in membrane bilayers, conferring resistance against solubilization by detergents, and can also be used for delivery of drug molecules in a lipophilic environment. 39 Synthetic analogue of Lipid A has been found to exhibit antitumour activity alongwith necrotizing effect. 40

Synthetic Nucleic Acids

These are synthetic alternatives to the naturally-occurring nucleic acids DNA and RNA, known as Xeno nucleic acid (XNA). However, conventional nucleic acid polymerases (DNA polymerase or RNA polymerase) are unable to process these synthetic nucleic acids. 20 Chemically, XNA is much different as compared to DNA and/or RNA.

XNA polymerases (Xenozymes or XNA-aptamers) can be listed as – XNA transliterase, reverse XNA transliterase, XNA replicase, XNA-transcriptase, XNA ligase, etc. 21

The synthetic nature of XNAs can be attributed to the replacement of deoxyribose and ribose residues respectively in a single nucleic acid unit. These sugars are replaced by those molecules which make the resultant nucleic acid “synthetic” or artificial – Arabinose (ANA), Fluorine with ANA (FANA), 23 Cyclohexene (CeNA), Threose (TNA), Locked (LNA), Peptide (PNA), Glycol (GNA), 1,5-anhydrohexitol (HNA). 24

Synthetic nitrogen bases have also been produced having the base pairing X-Y (not connected to sex chromosomes). These synthetic bases can be added to naturally occurring DNA bases present in Escherichia coli which results in the synthesis of artificial proteins consisting of upto 172 amino acids. 22

Significance of synthetic nucleic acids – 22

Forensics – The synthesis of artificial nucleic acids has led to the conclusion that the presence of DNA at any crime scene cannot be regarded as foolproof method of identification. DNA from an alternate source can be transferred or even artificially synthesized (from an already existing database) so as to tamper with the evidence originally present at any crime scene. In order to distinguish between tampered DNA and real DNA samples, a specialized test can be performed. This test checks for methylated DNA as marker for real DNA. Seventy percent of human DNA undergoes methylation as part of repression of gene expression. Synthetic DNA lacks methylated groups hence can be identified. 25

Vaccines – Vaccine against Dengue virus has been synthesized through engineering of synthetic DNA plasmids and modifying them suitably so as to express antibodies which neutralize dengue virus (also known as nAbs or neutralizing antibodies). 26 The method to introduce antigens present in vaccines containing synthetic nucleic acids comprises of the use of cytokine adjuvants produced through genetic engineering and delivery of synthetic plasmids through electroporation. These methods have been found to enhance both humoral and cell-mediated immune response. 27

Diagnostics – Synthetic DNA or RNA molecules (oligonucleotides containing 100 base pairs) can be used as reference controls for diagnostic tests, which are used for the detection of genetic disorders caused by mutation. 28 PNAs in combination with fluorescence in-situ hybridization (FISH) can be used as probes for germ cells such as spermatozoa, oocytes, as well as embryo at various stages of development (blastomeres), for the identification of chromosomes as well as the detection of chromosomal aberrations (such as aneuploidy). 29

Therapeutics – Exosomes existing on a nanoscale can be used for transfer of synthetic therapeutic nucleic acids across cells. This can be proposed to be an effective form of therapy against brain metabolic disorders. 30


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About Author / Additional Info:
I am a post-graduate in Biochemistry from the University of Mumbai