Therapeutic modalities

conventional small molecules
1. lipinski's rule of 5
  1. mol wt<500
  2. lipophilicity btwn -1 and +5
  3. hydrogen bond acceptors <10: O,N
  4. hydrogen bond donors < 5: NH,OH
2. types
  1. natural
    1. e.g. statins, opiates, antibiotics
      1. atorvastatin; lipitor
        HMG-CoA reductase inhibitor; cholesterol lowering
      2. penicillin: interrupts peptidoglycan wall cross linking
      3. Tetracycline: affecting 30S ribosome subunit
  2. synthetic
    1. most drugs
      1. e.g. omeprazole
  3. semisynthetic
    1. 2nd generation antibiotics
      1. e.g. penicillin derivatives; amoxycillin
3. advantages
  1. doctors and patients understand it
  2. chemical space is vast
  3. pharma knows how to produce, develop, purify, formulate, market... etc
  4. oral administration is possible
4. disadvantages
  1. toxic side effects due to low specificity
  2. low hanging fruits gone: increasing R and D expenditure, low drugs coming in
  3. an system complex and as such many mechanisms to get rid of foreign molecules
  4. oral absorption poor for many compounds
pharmacokinetics
1. AMDE
2. problem solved
  1. bioisosteres
    1. e.g. replace ester with amide
  2. pegylation, acylation
  3. conjugate transformation, biotransformation
  4. prodrugs
    1. inactive when administered, activated by metabolism
      1. hydrolysis, oxidation/ reduction
      2. too lipophilic
        derivatise
        take advantage of reductases in the body
      3. not lipophilic enough
        derivatise
        take advantage of oxidases in the body
      4. toxicity
        e.g aspirin causes ulcer
        aspirin prodrug: in body, active salicylic acid; pain killer
    2. e.g. lactone form of lovastatin
Biopharmaceuticals/Biologics
1. types
  1. type 1
    1. synthetic mimicing natural
      1. terlipressin
      2. salmon calcitonin
    2. recombinant DNA tech
      1. insulin
      2. growth hormone
      3. GMCSF, GCSF
    3. extracted from naturla sourcesl
      1. insulin
      2. growth hormone
    4. synthetic peptide disruptors
      1. velcade, synthetase inhib.
        velcade for multiple myeloma: 20 percent users cured
      2. Fuzeon: HIV entry inhibitor
  2. type 3
    1. DNA
      1. antisense oligos and siRNA
        e.g vitravene
        intraocular?
    2. Cell
      1. stem cell therapy
    3. tissue
      1. trachea, skin, bladder
        e.g. apligraft
      2. human donors, tissue engineering
    4. organ
      1. Tx: human donors
  3. type 2
    1. antibodies
      1. rabies, tetanus, snake venom, botox
      2. human and animal immunoglobulins for rapid immunomodulation
    2. monoclonal antibodies
      1. ritruximab
    3. enzymes
      1. dornase, galactosidase, cerebrosidase
        dornase for cystic fibrosis to dissolve mucus; inhalation
    4. vaccines
      1. types
        natural/cellular
        rec DNA tech
      2. rabies, tetanus, hep A
2. Advantages
  1. cheap and quick discovery
  2. no need for screening and optimization
  3. no contamination with prions and virions
  4. wide range
  5. biological so low side effects, low toxicity
  6. more specific
  7. no adverse immune response, can be expressed as human sequences
  8. higher success rate, low attrition rate
3. Disadvantages
  1. commercial scale: increased spend for purification and QC
  2. no or low oral administration; may need specialized delivery systems
  3. unconventional
  4. shelf life, in vivo half life, PK problems
  5. less consistent quality and yield: biological system
  6. many are species specific; so difficult efficacy testing
Peptides and Peptide disruptors
1. advantages
  1. low immunogenicity; low side effects
  2. high specificity: selective pharmacological interference
  3. low toxicity
  4. low discovery costs
  5. helps uunderstand molecular mechanism
2. diffiulties/disadvantages
  1. low availability
    1. solve by pegylation, acylation, encapsulation, other modifications
  2. low stability
    1. solve longevity issues by additives or lyophilization
  3. no oral administration
    1. instability in GIT
    2. subcutan, liposomal, intraocular, pulmonaryy, nasal
  4. does not cross blood brain barrier
  5. difficult to synthesize in large quantities; bulk production and purification issues
  6. some side effects; from site of injection, aggregation
  7. restricted membrane permeability
  8. rapid degradation
Disrupting protein-protein interactions
1. Small molecule
  1. Case study
    1. PKA-AKAP interaction
      1. current peptides known: Ht31, AKAP18 -L314E, AKAPis
        peptide issues
      2. AKAP anchors PKA to microdomain
        thereby compartmentalizing cAMP signaling
    2. Christian et al., 2010
      1. techniques used
        ELISA
        Surface plasmon resonance measuremtn
        NMR
        cAMP pull down assay
        Immunoprecipitation
    3. findings
      1. Direct interaction
      2. AKAP-PKA interaction is direct
      3. 20000 FMP small molecules Screened
      4. 19 hits, 9 hits validated, 2 taken further
        FMP-API-I chosen
        focussed library of 26 derivatives
        FMP-API-I and FMP-API-I/27
    4. allosteric inhibition
      1. allosteric regulatory sites: binding to the D/D domain of regulatory units
2. Peptides
  1. case study
    1. PDE4-HSP20 interaction
      1. HSP20 is cardioprotective
        constitutively phosphorylated mutant at ser16 prevents apoptosis by inhibiting caspase 3
        ischaemia/reperfusion, apoptosis....
        unphosphorylated mutant negates protective effects
        eads to overaccumulation of cAMP which has negative effects
        active when phosphorylated by cAMP dependent PKA
      2. PDE4 sequesters HSP20 thereby reducing inappropriate phosphorylation due to fluctuating basa; cAMP levels
      3. Other methods:
        Dominant -ve PDE4 constructs
        PDE4 knockout mice
        RNAi silencing
        PDE4 disruptor peptides
  2. Sin et al., 2011
    1. techniques used
      1. Immunopurification (activity)
      2. mmunopurification: Western blotting
      3. Cellulospots for peptide array
        to define HSP20 binding site with PDE4D5 sequence
      4. agarose pull down assay with overlay and BSA as control
    2. findings
      1. HSP20 and PDE4 coprecipitate
      2. manufactured disruptor Peptide 906 can disrupt interaction and scrambled version of same wt and charge peptide cont. cant
      3. PDE4 modulates cAMP flux in cellular compartment occupied by HSP20
      4. disruption protects against hypertrophy in cultured cardiac myocytes
3. Protein-protein interactions
  1. strengths
    1. highly specific pharmacological interference
    2. helps understand molecular mechaniams
  2. Challenges
    1. large interaction surfaces
    2. No defined cavities as in catalytic centres of enzymes or bnding pockets of receptors

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Therapeutic modalities

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	Created by Jumai Abioye almost 11 years ago