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Biotechnology > Therapeutics > Flashcards

Therapeutics Flashcards

1
Q

What is therapeutics?

A

Therapeutics: treatments used to alleviate or prevent a particular disease, e.g. drug therapy, medical devices, diagnostics
May be used in patients with active disease, in preventive medicine, or as palliative care

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2
Q

What are some examples of novel therapeutics from natural products?

A

Anti-cancer drugs
Analgesics
Novel diagnostic probes/proteins
Early examples throughout human history include oils from cedar, cypress and liquorice, as well as myrrh, poppy juice, honey

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3
Q

Why is marine biotechnology important?

A

A growing area in medical bioprospecting
High number of known species
Estimated majority of ocean species yet to be classified
>80% of oceans unmapped, unobserved and unexplored
Diverse niches e.g. hydrothermal vents
High level of chemical diversity

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4
Q

What is the drug biodiscovery pipeline?

A

Fundamental research from new species etc- many decades
Novel drugs
Target identification and screening- 5 years
Efficacy trials- 5 years
Regulatory approval- 1-2 years

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5
Q

What are the different methods for natural product discovery?

A

Top down approaches:
- Culture condition screening
- Diverse sampling
- Comparative metabolomic profiling

Bottom up approaches:
- Bioinformatics tools
- Native host
- Heterologous host

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6
Q

How are promising compounds evaluated as a potential drug?

A

Preclinical testing and evaluation stage
Chemical properties assessed, also synthesis and purification
Toxicology/pharmacology: in vitro and in vivo animal testing
Tests conducted on rodents and non-rodents
Includes tests on human cell lines or blood

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7
Q

What are the four key questions when assessing a promising compound?

A

How much is absorbed into the blood
How is it broken down in the body
What is the toxicity of it as well as any breakdown products
How quickly is it excreted

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8
Q

What phases exist during clinical trials?

A

Phase 1: 15-100 healthy volunteers tested for side effects, and optimum dose
Phase 2: 100-300 patients, consideration of effect that drug has on specific disease
Phase 3: between 100’s or 1000’s of randomized patients, compare new treatment with best available standard treatment
License granted- drug may now be prescribed
Phase 4: Long term risks and benefits, more knowledge about side-effects/safety

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9
Q

In novel therapeutics what are the possible targets for drugs?

A

Receptors/ion channels
Enzymes
Microtubules
DNA
Anti-inflammatory pathways

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10
Q

What is NF-kB?

A

Important transcription factor
NF-kB dimer of rel family proteins
Rel responsible for interactions of transcription factors with cytoplasmic proteins and DNA
Signalling pathways and transcription factors involved in many cancers arthritis, AIDS, Alzeheimers

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11
Q

What are examples of novel therapeutics from a marine sponge?

A

Two anti-cancer and anti-viral, drugs:
Ara-C (cytarabine)
Ara-A (vidarabine)

Source Organism:
The Caribbean sponge Cryptothethia crypta

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12
Q

What’s different in sponges?

A

Nucleosides normally bound to nucleic acids. Sponge nucleosides unusual as they exist in a free state

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13
Q

When was Ara-C synthesized?

A

1959: belongs to the category of drugs known as anthracyclines, and is a pyrimidine analogue
Ara-C converted into the triphosphate form within the cell, competes with cytidine to incorporate itself in the DNA
Sugar moiety of Ara-C hinders the rotation of the molecule within the DNA, stopping replication
DNA replication and repair also blocked due to the inhibition of DNA polymerase by Ara-C

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14
Q

When was Ara-C approved and for what?

A

Approved by FDA 1969 for leukemia
Still in use for leukemia
Can cross blood-brain barrier, so is also used in treatment of central nervous system lymphomas

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15
Q

When was Ara-A approved and what for?

A

Approved 1976 as antiviral drug, active against herpes
Ara-A becomes triphosphated in cells and competitively inhibits viral DNA polymerase, leading to formation of faulty DNA

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16
Q

What anti cancer drugs come from ascidians?

A

Family of alkaloids named ecteinascidians
Anti tumour activity of the extracts reported 1969, structure not established until 1990
Estimated that 1 ton of the animal needed to yield 1g

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17
Q

What are the major natural compounds in the ascidians?

A

Ecteinascidian-743: most abundant natural component
ET-729: analogue, similar potency, less abundant

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18
Q

What is the mode of action of the ecteinascidins?

A

Mode of action: covalent modification of DNA
Selective for GC-rich sequences
Interacts with nuclear Excision Repair (NER) system proteins
Also shown to inhibit pro-inflammatory cytokines in vitro

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19
Q

What does Ecteinascidin 743 do?

A

May prevent tumours from becoming resistant to chemotherapy/ Interferes with gene producing P-glycoprotein
Approved under trade name Yondelis for advanced soft tissue sarcoma, ovarian cancer, in phase 2 for breast cancer

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20
Q

What’s another example of an anti-cancer drug from sponges?

A

Natural compound Halicondrin B
Discovered from rare sponge Halichondria okadai in 1986
Cytotoxicity to murine leukemia cells observed at nM conc
Binds to tubulin, blocks formation of microtubules, cell dies via apoptosis

21
Q

What do microtubules contribute to?

A

Contribute to formation of the mitotic spindle
Cell stops in G2/M phase of cell cycle
Mitotic spindles disrupted, cell death occurs from prolonged mitotic blockage

22
Q

What is an example of anti cancer drug from molluscs?

A

Natural compound Dolostatin 10
Discovered 1972
Peptides derive from dietary cyanobacteria
Principal mode of action- binds to tubulin, preventing microtubule formation and thus mitosis
Synthesis achieved in 1989

23
Q

What is Prialt?

A

Derived from conotoxins- obtained from venom glands of the cone shell, conus
Each cone shell contains 100-200 small disulfide-bridged peptides in the venom. Produced by several gene superfamilies

24
Q

What does Prialt act on?

A

Act on subtypes of ion channels
Peptides short, synthetic derivatives relatively easy to produce

25
Q

What is Analgesic produced from?

A

Ziconotide
Synthetic derivative of gamma conotoxin
Estimated to be from 50-1000x more effective than morphine, avoids dependence
Reversibly blocks N-type calcium channels located on primary nociceptive afferent nerves on the spinal cord
Conotoxins also used as standard neuroscience research tools

26
Q

What is Prialt’s mode of action?

A

Currently used to treat severe chronic pain in adults who can’t take other treatments, or when other treatments do not work, stop working or cause side effects
Administration by intrathecal infusion (into spinal fluid)
Side effects can be severe, including psychiatric symptoms, memory problems, speech impairment

27
Q

What are carrageenans?

A

A group of polysaccharides, which are repeating sequences of sulphated galactose
Divided into 6 groups, based on degree of sulphation, extraction methods and solubilities: kappa, iota, lambda, mu, nu, beta, and Theta carrageenans

28
Q

Why are carrageenans valuable?

A

Valuable in the food industry because of their moisture binding and stabilizing properties. Widely used to control consistency/texture of food, toothpaste, gel products and commonly used in milk products

29
Q

Where are carrageenans obtained from?

A

Obtained from several red algae
Potent inflammatory properties, which has caused some controversy over associations with gut inflammatory disorders

30
Q

What were carrageenans developed into?

A

Developed into an anti-viral nasal spray
Sold as over the counter lozenges, oral and nasal spray preparations

31
Q

What is endotoxin used for?

A

1971: Standard Limulus-amoebocyte lysate test (LAL) devloped
1977: FDA replaces standard test for endotoxins with the LAL test
Used to detect bacterial toxins in injectable drugs, irrigation fluids, surgical tubing, IVF, vaccines

31
Q

What is a biologic?

A

A biologic is manufactured in a living system e.g. a microorganism, or plant or animal cells e.g. monoclonal antibodies, hormones, growth factors
Majority of biologics are large, complex molecules or mixtures of these
Many produced using recombinant DNA technology

31
Q

What does carrageenan act as?

A

Carrageenan acts as a shield, preventing interaction with mucosa and cell infection
Viral material bound by carrageenan shed from mucosa by muco-ciliary clearance
Recent studies have shown potential of iota-carrageenan to stop replication of SARS-Cov2 in vitro

31
Q

What was derived from the jellyfish Aequorea victoria?

A

Green Fluorescent Protein (GFP)
Contains an auto-fluorescent protein, known as GFP
GFP applied to track single proteins inside cells: e.g illuminate growing cancer tumours, show the development of Alzheimer’s in the brain, or the growth of pathogenic bacteria

32
Q

What dominates the biologic sector?

A

Antibodies dominate the sector, highest revenues derived from mammalian mAbs (monoclonal antibodies)
Success of Mabs relates to: (1) High specificity; (2) high affinity; (3) long serum half-life; (4) amenability to molecular engineering

32
Q

What is the history of endotoxin and horseshoe crabs?

A

1880: W.H. Lowell first studies coagulation of L. polyphemus blood at Johns Hopkins University
1956: Frederick Bang discovers that horseshoe crab blood forms clots when bacteria are present
1964: Discovered that the blood clotting agent in horseshoe crabs is an amoebocyte
1968: Discovered that endotoxin causes clotting reaction

33
Q

What is the process of LAL production?

A

Horseshoe crabs caught, haemolymph extracted, then centrifuged to separate amoebocytes and plasma
Amoebocytes freeze-dried and processed
Studies claim that bled crabs have a relatively low mortality rate

34
Q

What do Agnathans (jawless fish) possess?

A

Possess lymphocytes, but do not produce immunoglobulin antibodies
After injection of xenoproteins, microbial carbohydrates etc, the lymphocytes express hook-shaped proteins:
Variable Lymphocyte Receptors (VLR’s)
Can be on cell surface or secreted into fluids

35
Q

What are lambodies?

A

Proteins capable of binding glycans in many applications e.g. imaging, drug delivery, control of carbohydrate mediated processes
Currently available mammalian antibodies- poor affinity for carbohydrate antigens
Importance in biomedicine: many tumour cells display glycoproteins with abnormal glycosylation

36
Q

What are many tumour associated carbohydrates?

A

Truncated glycans
These glycans associated with mucin-type glycoproteins in 90% of human cancers but are absent from nearly all normal tissues

37
Q

How can CLL be monitored?

A

Lampreys immunized with lymphocytes from CLL patients
A recombinant VLR antibody is generated, specific for the CLL donor cells
VLR Ab used to moniotr the CLL donor after chemoimmunotherapy-induced remission
Re-emergence of leukemic clone detected months later, faster than standard diagnostic markers
Offers rapid strategy for generating probes for early detection of leukemia recurrence

38
Q

What do sharks possess?

A

Sharks express a primordial antigen receptor:
IgNAR in which immunoglobulin cassettes replace leucine-rich repeat (LRR) cassettes of VLRs
Phage and yeast display have been used successfully as robust and reliable selection platforms to express IgNARs

39
Q

What’s unique about IgNARs?

A

Highly thermostable
IgNARs can be heated (>80 degrees, up to 1 hour) and retain ability to bind target when returned to physiological conditions

40
Q

How are conventional Mabs limited in some aspects?

A

Tissue penetration of conventional Ab constrained by large size
Slow tumour penetration as well as non-specific uptake by healthy tissues

41
Q

What are the potential advantages of shark NARs?

A

Tremendous diversity
Stable proteins
Greater mobility for tissue penetration
Greater predisposition to target antigens

42
Q

What do camelids produce?

A

Camelids produce conventional antibody (heavy chains, 2 light chains) as well as heavy chain IgG
Also known as single domain antibodies or nanobodies

43
Q

How are nanobodies produced?

A

A drop of blood is taken from a llama
Blood contains many different Ab, of which a few bind to the virus
Ab are engineered to create nanobodies with high affinity binding
The nanobodies are specific for the spike protein

44
Q

How do nanobodies work?

A

Normally, the spike protein binds to the ACE-2 receptor, infecting human cells
The nanobody binds to the spike and blocks entry into the cell
SARS-CoV-2 virus, illustrating spike proteins

Biotechnology (12 decks)

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