Carbohydrates

Question 1

Carbohydrates

Answer 1

They are a large group of biomolecules that include sugars, starch and cellulose.
They are hydrolysed hydrocarbons, characterised by the fact that every carbon is bonded to an oxygen atom.

Question 2

Monosaccharides

Answer 2

(or single sugars) are the simplest carbohydrate monomer. They can exist as structural isomers and are often chiral.

Question 3

What can Glucose monomer units form?

Answer 3

Polymeric structures, such as cellulose and starch. These are termed polysaccharides or glycans. The conversion of glucose from the ‘long-chain’ form to the ring structure, two structural ring isomers can be formed, denoted α and β, based on the orientation of the hydroxyls. This subtle difference in how the ring forms, gives rise to different polymer products: α glucose forms starch and β glucose forms cellulose. The important point to take away is the sheer number of different glycans that can form (α, β, branched).

Question 4

Why have Carbohydrates have drawn far less attention as drug targets compared to nucleic acids and proteins?

Answer 4

This is due to our lack of understanding of fundamental glyco- (carbohydrate) biology. However, recent changes in analytical and synthetic techniques are revolutionising the field.

Question 5

What Carbohydrate-based therapies are currently being developed?

Answer 5

For a number of diseases, including cancer, bacterial infections, AIDS, diabetes, influenza and rheumatoid arthritis.

Question 6

Glycans

Answer 6

Monosaccharides linked ‘glycosidically’ through an oxygen linker. These glucose polymers can be highly branched. Glycans are largely found on the exterior of cell walls, often bound to proteins

Question 7

lectins

Answer 7

Glycans can bind to peptides to form glycopeptides, to lipids to form glycolipids and to proteins. Carbohydrate-binding proteins. Lectins are a diverse group of proteins that bind to biomolecules that contain carbohydrate groups. Lectins are found in varying densities on all cell-surface membranes. They form highly specific interactions with carbohydrates through hydrogen bonding, metal coordination, van der Waals forces and hydrophobic interactions

Question 8

sialic acid

Answer 8

N-Acetylneuraminic acid (NeuAc) is a carbohydrate present on the surface of cells that binds to the influenza virus.

A nine-carbon monosaccharide with several functional groups. Its structure consists of a six-membered ring with an acetamido group (-NHCOCH3) attached to the second carbon and a carboxyl group (-COOH) attached to the first carbon. It also has a hydroxyl group (-OH) attached to the third carbon and a glycerol side chain attached to the fifth carbon.

The presence of the acetamido group and carboxyl group makes NeuAc acidic, hence the name “sialic acid.” Its structure is similar to other neuraminic acids, differing mainly in the presence of the N-acetyl group.

Question 9

How does the influenza virus binds to host cells?

Answer 9

Through a specific interaction between the viral surface protein called hemagglutinin (HA) and sialic acid receptors on the host cell surface.

Question 10

How does NeuAc link to the influenza virus?

Answer 10

NeuAc, being the most common form of sialic acid in humans, serves as the primary receptor for influenza viruses.

Question 11

The surface of influenza virus pathogens are covered in two proteins:

Answer 11

Hemagglutinin lectins and neuraminidase (also called sialidases). Both proteins bind to NeuAc, Hemagglutinin via the surface of the protein and neuraminidase via a deeper binding pocket. Hemagglutinin initially binds to NeuAc, before neuraminidase cleaves the sialic acid.

Question 12

What happens by binding to the sialic acid receptors?

Answer 12

The influenza virus gains entry into host cells and initiates the infection process.

Question 13

What does a subsequent protein conformation change hemagglutinin cause?

Answer 13

Infection to advance from the viral cell into the healthy cell

Question 14

What does Anti-influenza drug design focused on?

Answer 14

The inhibition of both hemagglutinin and neuraminidase. Zanamivir and oseltamivir (Tamiflu) are antiviral drugs that inhibit neuraminidase. They mimic the transition state of the enzymatic hydrolysis reaction that cleaves NeuAc.

Question 15

Zanamivir

Answer 15

First neuraminidase inhibitor to be brought to market
Marketed by GSK, 1999.
Inhaled administration
Only 2% bioavailability
Concerns over efficacy: May not be any more effective than a placebo
An example of where computational chemistry played a key role in identifying and optimising the molecule.

Question 16

Oseltamivir

Answer 16

Second neuraminidase inhibitor to be brought to market - just after zanamivir
Developed by Gilead and marketed by Roche, 1999
Oral administration
80% bioavailability
For patients at high risk.

Question 17

What influenza drugs are administered today for ‘at risk’ patients?

Answer 17

Tamiflu and, to a lesser extent, zanamivir are administered today as flu treatments for ‘at risk’ patients. They are effective if the disease is still in its infancy.

Question 18

What other factors other then NeuAc as a receptor for influenza virus binding contribute to the infection process?

Answer 18

This is just one aspect of the complex interactions between the virus and the host. Other factors, such as the immune response and viral replication mechanisms.

Question 19

Vancomycin

Answer 19

A glycopeptide: a carbohydrate linked to a peptide chain. First marketed in 1954 it is an intravenous antibiotic, often used as a last resort.

Question 20

How do Glycopeptides and β-lactam antibiotics both work?

Answer 20

By interrupting the mechanism of bacterial cell wall synthesis. β-lactam antibiotics bind to enzymes involved in peptidoglycan synthesis. Whereas glycopeptides such as Vancomycin attach to the ends of the growing peptide chains between the peptidoglycan layers. Vancomycin works best for gram positive bacteria because the peptidoglycan layer is on the outside of the cell wall.

Question 21

Where does Vancomycin bind to ?

Answer 21

To the ends of the peptide links that grow between the peptidoglycan layers.

Question 22

What is Vancomycin?

Answer 22

A glycopeptide antibiotic that inhibits cell wall synthesis in Gram-positive bacteria. It achieves this by binding to the D-Ala-D-Ala terminus of the growing peptidoglycan chain, effectively blocking the transpeptidase enzyme responsible for cross-linking the peptidoglycan strands.

Question 23

The problem with vancomycin and how have researcher tried to combat the issue?

Answer 23

Vancomycin is an old drug and suffers from antibiotic resistance. Recently, researchers from Scripps in the US have modified vancomycin to develop three compounds that may be antibiotic-resistant. This is made possible by recent advances in the synthesis of carbohydrates. Although this 2017 finding is a long way off from being tested in the clinic, it shows how advances in chemistry can open up the field of pharmaceutical research with 60-year-old drugs.

Question 24

What changes to vancomycin did researcher make?

Answer 24

The authors describe a series of studies that aimed to modify vancomycin, an antibiotic, to address the molecular basis of resistance to the drug.
The modifications involved changing a single atom site in the drug’s target binding pocket, specifically the residue 4 carbonyl O to S, NH, or H2.
These modifications allowed the drug to bind to the altered target D-Ala-D-Lac while maintaining a binding affinity for the unaltered target D-Ala-D-Ala, resulting in dual-target binding compounds.
The dual target binding compounds were effective against vancomycin-resistant organisms that use D-Ala-D-Lac peptidoglycan precursors and remained active against vancomycin-sensitive bacteria.
The potency of these compounds correlated with their dual binding affinities for model target ligands.

Question 25

Erythromycin

Answer 25

A macrolide antibiotic. Macrolides are sugars attached to a large 14+ carbon ring.

Question 26

What covers the surface of any cell?

Answer 26

Bacteria and pathogens are covered in proteins and branched carbohydrates - like a dense forest. When a foreign cell is detected our immune response creates highly specific antigens that bind to the proteins and/or carbohydrates, flagging the cell for destruction.

Question 27

How do vaccines work?

Answer 27

Vaccines replicate these ‘disease’ proteins or carbohydrates, to allow the body to create the blueprint for the appropriate antigens in readiness to fight the disease.

Question 28

How are carbohydrates being used in vaccines?

Answer 28

Traditionally, carbohydrates have been difficult to create vaccines for because of their synthetic complexity.

However, with new synthetic techniques carbohydrate vaccine research is booming. Synthetic carbohydrate vaccines are being developed for malaria, influenza, pneumonia, HIV and cancer.

Question 29

Glycomimetics

Answer 29

These are small molecule drugs that mimic the function of a carbohydrate.

Question 30

Why have Small molecules have long been a favourite of drug designers?

Answer 30

They have drug-like properties: good absorption, good solubility and PK/PD profiles suitable for once or twice daily oral administration.

Question 31

How are carbohydrates different to small moclecules?

Answer 31

By contrast, carbohydrates are large, highly polar molecules with very poor cell permeability and are unsuitable for oral administration.

Question 32

in more detail what are glycomemetrics?

Answer 32

Glycomimetics, synthetic compounds designed to mimic carbohydrates, have gained significant attention in drug development due to their potential applications in various therapeutic areas.

Question 33

recent study using glycomimetic as an anti-cancer therapy

Answer 33

one recent study focused on developing glycomimetic inhibitors targeting galectins, a family of proteins involved in cancer progression and metastasis. These inhibitors showed promising results in preclinical models by inhibiting galectin-mediated tumor growth and metastasis

Question 34

What are they mechanisms of action for glycomimetic in anti cancer therepy?

Answer 34

Glycomimetics targeting cancer-related proteins can interfere with crucial cellular processes such as cell adhesion, migration, and signaling pathways, thereby inhibiting tumor growth and metastasis. By selectively targeting specific carbohydrate-binding proteins, glycomimetics offer a unique approach to cancer therapy.

Question 35

In the field of anti-inflammatory therapeutics how have glycomimetics been used?

Answer 35

They have shown potential as inhibitors of selectin-mediated cell adhesion. Selectins are involved in the recruitment of immune cells to sites of inflammation. Researchers have developed glycomimetics that mimic the carbohydrate ligands recognized by selectins, effectively blocking the adhesion of immune cells and reducing inflammation in preclinical models.

Question 36

In the field of anti-inflammatory therapeutics how have glycomimetics been used?

Answer 36

By blocking selectin-mediated cell adhesion, glycomimetics can modulate the recruitment of immune cells to inflamed tissues, reducing the inflammatory response. This targeted approach has the potential to minimize the side effects associated with systemic inflammation inhibition.

Question 37

What are the Ongoing efforts towards the Glycomimetic Antivirals against HIV and Influenza?

Answer 37

Glycomimetics have also shown promise as potential antiviral agents against HIV and influenza viruses. Researchers are actively exploring the development of glycomimetics that can inhibit viral entry by targeting viral envelope glycoproteins. By mimicking the carbohydrate receptors on host cells, these glycomimetics can interfere with viral attachment and fusion, potentially inhibiting viral infection.

Question 38

What are the Challenges and potential benefits of Glycomimetic Antivirals against HIV and Influenza?

Answer 38

Developing glycomimetic antivirals is challenging due to the complex interactions between viral envelope glycoproteins and host cell receptors. However, rational design and in silico screening techniques have been instrumental in identifying glycomimetic hits with improved affinity and specificity for viral targets. Glycomimetics offer the advantage of targeting conserved regions on viral glycoproteins, reducing the likelihood of viral resistance development.

Question 39

In Silico Screening in Glycomimetic Discovery:

Answer 39

In the search for potential glycomimetic hits, computational methods such as molecular docking and virtual screening are widely employed. These techniques involve the use of computer algorithms and libraries of chemical structures to predict the binding affinity of glycomimetics to target proteins. In silico screening helps prioritize compounds for further experimental validation

Question 40

Rational Design in Glycomimetic Discovery:

Answer 40

Rational design involves the deliberate modification of glycomimetic structures based on a deep understanding of the target protein’s binding site and interactions. By utilizing structural information and computational modeling, researchers can optimize glycomimetics to enhance their efficacy, specificity, and pharmacokinetic properties.

Question 41

Prodrug Strategies for Glycomimetics, Improving pharmacokinetics:

Answer 41

Glycomimetics, like many other drug compounds, can face challenges related to their pharmacokinetic properties, such as poor solubility, rapid metabolism, or limited bioavailability. Prodrug strategies offer a solution by modifying the glycomimetic structure to improve these properties. For example, the addition of specific functional groups can enhance solubility or increase membrane permeability, improving drug delivery and bioavailability

Question 42

Prodrug Strategies for Glycomimetics, Prodrug activation:

Answer 42

Prodrugs are designed to be biologically inactive until they undergo enzymatic or chemical conversion in the body to release the active drug. By employing prodrug strategies, researchers can optimize the pharmacokinetic profile of glycomimetics and enhance their therapeutic potential.