PCL 120 Final

Comirnaty vaccine (BioNtzer & pfizer)

mRNA that encodes spike protein enclosed in lipid nanoparticle (patient converts mRNA to protein and mounts immune response)

What were the two comirnaty vaccines tested and which one made it to the market?

BNT162b1 and BNT162b2, only the latter made it to phase 2

Spikevax vaccine (Moderna)

mRNA encodes the spike protein enclosed in lipid nanoparticle

How long did it take for SARS-CoV-2 vaccines get approved?

less than eight months after trial started, achieved by overlapping trials

mRNA vaccines for COVid-19 , which two won the Nobel Price?

Katalin Kariko and Drew Weissman

Main components of COVID-19 vaccine

mRNA, Lipids, salts, acetic acid and amines, sugar

Medicago’s plant-based COVID-19 vaccine

Virus like particles made in plants, harvested and purified, only 71% efficacy but did not bring vaccine to market because of financial and production issues

Nuvaxovid (novovax)

Protein-based vaccine that contains spike protein produced by insect cells. immune system stimulant derived from tree

Initial response for small molecule drug treatments was largely based on ___

repurposing drugs; using existing drug or preclinical chemical compound for new purpose

Remesivir

Oringinally produced to treat Ebola, needs to be metabolized to become active, no added benefit

Lopinavir-ritonavir

Used for treatment of HIV/AIDS, protease inhibitor, no added benefit

Chloroquine/hydroxychloroquine

anti-malarial drug, increases pH and lysosomes, no added benefit

Paxlovid

Oral antiviral med for COVID, inhibits enzyme needed for virus replication, blocks protease

PK boosters

compounds used in combination with primary therapeutic agent that does not directly affect disease but enhance activity of primary agent

What is the component of paxlovid that affects the PK of nirmatrelvir?

Ritonavir

Long COVID

Symptoms of COVID19 persist for more than 12 weeks after infection, 15% adults who contracted VOD-19 experienced long symptoms 3 or more months after

What are the 3 long covid intervention clinical trials being tested?

1. intravenous antibodies

2. Oral pill to to treat heart rate

3. High-salt diet

___ are the most common form of genetic variability

Single nucleotide polymorphism (SNPs); single base changes in DNA

Pharmacogenomics

study of drug response based on genetic makeup and variability

ADME can explain pharmacokinetics:

Absorption, distribution, metabolism, excretion

Pharmacological and toxicological consequences of drug metabolism

Inactivation: active drug to inactive product

Activation: inactive pro-drug to active product

Maintenance of activity

Increased chemical reacitvity

___ enzymes act on drugs to help eliminate them. Usually the enzymatic reaction results in a more ___ product

Hepatic enzymes; water-soluble

Case study: morphine poisoning in breast-fed infant

Infant died from morphine poisoning, mother been prescribed codeine and paracetamol after birth for pain, genotyping analysis of CYPD6 shows the mother is ultra-rapid metabolizers

Case study: HER2 overexpression

IN patients with breast cancer testing for HER2 overexpression can improve treatment success, about 20% breast cancer are HER2-positive

Three FDA approved smoking cessation treatments exist:

1. Vareniclikne

2. Nicotine replacement therapy

3. Bupropion

Case study: optimizing smoking cessation treatments based on smoker’s nicotine metabolism

Increase in CYP2A6 activity = increase in NMR = increase in nicotine clearance

relative treatment efficacy quantified using odds ratio = proportion of event taking place in on group relative to another

Case study: IMPACT study uses genetic testing to identify genetic variants that can influence response to psychiatric medications

Tests 8 genes, saliva sample, provides recommendations re: 33 antidepressant/antipsychotic medications

How does genomic information for each patient recorded?

Once patient has been genotyped, the digital info is centralized, and checking patient sequence becomes electronic event

HepC drugs common in Canada that can be used for all HepC virus genotypes

Genotype-specific HepC drugs common in Canada too

Project GRADIENT

Genomic Research Approach for Diversity and optimizing Therapeutics; use of personalized medicine in researching and understanding genetic diversity in Africa

Genetic variability can affect the ___ and ___ properties of a drug

pharmacodynamic; pharmacokinetic

There remain ___, ___, and ___ challenges with the widespread use of personalized medicine

Logistical; ethical; language/communication

There is an increase/decrease in approval of personalized medicine by the FDA

Increase

Challenges for most drugs for brain health is the ___

blood-brain barrier

Major depressive disorder (MDD)

Treatment involves antidepressant therapy and psychotherapy

1/3 patients have inadequate response to treatment → treatment resistant depression (TRD)

Psilocybin assisted psychotherapy (PAP)

1. Preparation: participant meet with clinician

2. Dosing: after receiving drug, monitored and listening to music

3. Integration: participant meets with clinician in the weeks following

How does psychedelic mushrooms work

substituted tryptamines; body converts the inactive prodrug psilocybin to the active form psilocin

What is classified as a ‘serotonergic psychedelic” which works by binding and stimulating the serotonin 2A receptor, promoting neuroplasticity?

Psilocybin

Ketamine

A type of NMDA receptor blocker, changes the sympathetic nervous system, common used as anesthesia and depression

Ketamine is highly ___, can readily cross blood brain barrier

Lipophilic

Drug schedules in USA

Schedule I:

• Medical use: X

• Abuse: !

• Addiction !

Schedule V:

• Medical use: yes

• Abuse: no

• Addiction no

What is LSD and what schedule is it?

Its a hallucinogenic drug, type of psychedelics; schedule I, meaning it can not be used for medical reasons

Generalized anxiety disorder (GAD) and LSD

• second most common mental illness in adults

• New LSD compound given breakthrough designation by FDA

Drug targets of LSD

• serotonin 2A receptor agonist

• dopamine D1 and D2 receptor

• “trip” persists long after the drug is gone

Medicines Discovery Catapult

Includes 7 major pharmaceutical companies, and 2 large health charity organizations that work towards drug development for mental health

Thalidomide stops ___ development int the limb bud and caused ___ in thousands of children worldwide

blood vessel; phocomelia

what percentage of FDA approved drugs from 1980 to 2010 lack sufficient safety data for use in pregnancy?

>90%

FDA pregnancy exposure registries

Type of post-marketing surveillance, collects info on exposure during pregnancy and outcomes, then compare with women who did not take medication.

Subject to selection bias

Postpartum depression drug

First oral treatment for postpartum depression in 2023.

Synthetic neurosteroid that acts on GABA-A (calming)

Implies mechanisms of postpartum depression is different than MDD

Challenges of drug research in children

1. patient recruitment

2. consent

3. Children are not little adults

4. ethical issues

Ivacaftor treatment for cystic fibrosis

161 children with cystic fibrosis with specific mutation in chloride channel gene.

lung function is significantly improved with Ivacaftor. Quality of life improved

Company may receive ___ months of additional patent life if they conduct required studies for children. Huge benefit/cost ratio.

6

Neglected tropical diseases;

1. protozoa

2. bacteria

3. helminth (worm)

4. virus

River blindness

• caused by parasites

• moxidectin' approved 2018

• Better than Ivermectin

• Low or no skin microfilariae reduces transmission

Sleeping sickness

• caused by parasites in infected tsetse flies

• Fexinidazole: new 10 day oral med

• Earlier challenge: needed lumbar puncture to determine what stage of disease the patient has

Machine learning

1. provide examples of what is a cat and what is not

2. then ask machine to label new things

3. well suited to ineffable (too great to be expressed in words) things

Machine learning and AI automates the ____

ineffable

AI for in silico drug discovery and drug screening

digital protein structures + digital versions of chemical libraries

case study for drug targets

using AI to study protein-protein interactions by disrupting it

AI at U of T is…

• independent, not-for-profit corporation

• Laughed in march 2017

AlphaFold

AI that predicts protein structure from amino acid sequence

Trial pathfinder

AI tool that uses electronic medical records and patient data to optimize the selection of eligibility criteria to expand inclusion criteria for cancer clinical trials

GLP-1 (glucagon-like peptide 1) Receptor agonist drugs

• treats type 2 diabetes

• reduces risks shown with type 2 diabetes

• GLP receptor in brain

• Makes patient want to eat less (ozempic)

• First combination GLP + GIP is tirzepatide

What cells secrete insulin after sensing glucose level too high？

beta cells

Victoria gray

• 34, suffering with sickle cell disease

• can’t walk, sharp pains all over body, damaged her heart already

• cells removed from bone marrow

• Crispr used to edit cells

• billions of cells infused back into body

• Call her new cells “super cells”

• New bone marrow cells are creating normal blood cells

• Too expensive, costs 2.2 million per patient

CRISPR

• bacteria version of immune system can be used to reprogram genes in human cells

• Promise of CRISPR is to change DNA any way you want

• Change one base pair at a targeted site

COVID

KP2 strain is more effective; 80% protection against current strains

Orphoglipron

• Small molecule chemical version of GLP-1 receptor agonists

Peptides generally not stable when taken orally because it rapidly degrades in the ___

GI tract

Bacterial production of insulin using genetic engineering with human DNA

Insulin gene inserted into plasmid which is then collected

Car-T cell therapy

T-cells removed, altered to have receptors called CAR, grown then introduced into bloodstream

Dopaminergic neuron precursors

• derived from human embryonic stem cells, They are specialized neural stem cells that differentiate into dopamine-producing cells found in the brain

Antibody structure: what are its two regions

1. variable region:  recognizes and binds the antigen

2. Constant region: determines the mechanism used to destroy the antigen

Monoclonal antibody (mAbs)

• identical antibodies derived from a single antibody-producing cell (or clones of that cell)

Polyclonal antibodies:

complex mixture of antibodies produced by many different antibody producing cells

mAb production process requires the target antigen to be injected into a ___ and the Ab-producing cells to be fused with ___

mouse; immortal cancer cells

Recombinant DNA technology

•  can be used to modify mouse mAbs, enhancing their resemblance to human antibodies and reducing the risk of adverse immune reactions

Remicade mechanism of action

remicade reduces signs of autoimmune diseases by inactivating TNF-alpha

R0 tells us how contagious a disease is

• Average # of individuals that get infected from one infectious person

• Ideally, we want R0 < 1

SCAGO

sickle cell awareness group of Ontario

Drug identifiation steps

program selection

Drug target

disease/mechanism

target protein (druggable?)

chemicals

safety in at least two animal species

Patent protection

20 years

Cost to get drug to market

>2B 15 years

surrogate endpoint

indiator that tells if treatment worked or not

T cells vs. B cells

Kill vs creat antibodies

All of us

DNA from 1 million people USA

• The Silent Genomes Project:

Library of DNA from indigenous people