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A real example:

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... particularly AMPs AMPs = Antimicrobial Peptides 15-30 ... Answer to antibiotic resistance? Molecular diversity dependent on ... mechanism) Peptide (oligo ... – PowerPoint PPT presentation

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Title: A real example:


1
A real example
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Natural Product Peptides, Peptidomimetics
Peptide Analogues
  • Natural Product Peptides (nonribosomal
    peptides)
  • Product of secondary metabolism
  • Synthesized on the NRPS
  • Numerous pharmaceutically relevant peptides

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More Nonribosomal Peptides
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  • Chemical synthesis demonstrated on solid support
  • Synthesis weeks (soln) ? days (solid)
  • Employ more and/or different protecting groups
  • Unusual functional groups
  • Cyclization on resin?
  • Other modifications (i.e. sugar moiety)?
  • Solid-supported synthesis has allowed the
    substitution and/or modification of AAs ?
    analogues
  • AA, functional groups, stereochemistry,
    substitution, etc
  • Study structure-activity relationships
  • Potential therapeutics
  • Note Industrial synthesis not performed on
    solid supported

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Peptide Analogues
  • Recently, there have been developments in the
    modification of peptides, particularly AMPs
  • AMPs Antimicrobial Peptides
  • 15-30 AAs in length
  • Produced by all animals (insects to frogs to
    humans)
  • First line of defense against microbial organisms
  • Answer to antibiotic resistance?
  • Molecular diversity ? dependent on structure

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AMP Structure
  • Large proportion of hydrophobic residues (
    50 )
  • Also contain varying amounts of Lys, Arg His ?
    vely charged AAs
  • These AAs vary in their arrangement within the
    peptide
  • This arrangement of AAs allows disruption of
    bacterial membranes (anionic)

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Teflon? Peptide Fluorogainin-1
  • Fluorous analogue of the AMP, magainin (isolated
    from the skin of frogs)
  • Replaced hydrophobic residues (i.e., Val,
    Leu,etc) with fluorinated versions ? Teflon
    like
  • Resulted in more stable peptides
  • More resistant to unfolding by chemical
    denaturants heat
  • NMR also showed higher structural integrity
  • Results also indicated increased antimicrobial
    activity
  • Likely due to the increased hydrophobicity of
    peptide
  • This strong hydrophobic interaction may make the
    peptide less susceptible to proteases

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magainin series sites of fluorination Leu 6,
Ala 9, Gly 13, Val 17, and Ile 20
NMR structure of magainin 2
Other Analogues
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Peptidomimetics
  • Peptide mimics
  • Contain non-natural peptidic structural elements
    (i.e. peptide bonds or unusual functional groups)
  • Molecules vary in size structure
  • Commonly synthesized using Merrifield resin to
    study structure-activity relationships
  • Possible drug candidates

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Examples of Peptidomimetics
Mimic ?-sheets
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Peptide Synthesis in the Prebiotic World
  • Recall
  • Murchison Meteorite
  • Possible source of AAs (via the Strecker
    mechanism)
  • Peptide (oligo) formation ?
  • Selection of an enantiomer
  • Selection by crystal faces
  • Circularly polarized light from stars
  • Enantioenrichment
  • Via Serine octamer
  • Enrichment by sublimation

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Peptide Synthesis in the Prebiotic World
  • Also recall formation of peptides from
    monomers is energetically unfavorable (i.e.,
    ?Ggt0)
  • Modern world ? enzymes
  • Chemical synthesis ? activation strategies
  • Prebiotic world ? some energy input needed?
  • Possibilities?
  • Synthesis with minerals!
  • Clay has been shown to catalyze the condensation
    of Gly to peptides up to (Gly)6

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  • The experiment
  • Uses SFM (scanning force microscopy)

Apply gly to surface
Faults (cracks)
(at STP)
  • No visible change in faults or layers
  • HPLC showed no gly peptides

Hectorite (layered silicate) containing Mg2, Li
Cu2
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Experiment (cont)
Small glycine peptides (oligomers)
Apply gly to surface
Alternate cycles of heating to 90 C ddH2O
HPLC
Gly peptides of up to 6 AAs in length
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Other Similar Experiments
Varying the mineral can give different peptides!
  • Another experiment
  • Mixed NaCl Clay (mineral) heat
  • NaCl alone gave only short peptides
  • When clay was added, longer peptides were
    produced!

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  • Hadean Beach the primary pump
  • This resembles many of the features of chemical
    peptide synthesis
  • Step 1 In aqueous phase (i.e., ocean), 25 C
  • Similar to Wohler synthesis of urea
  • Amino group is now less reactive (amide-like)

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  • Step 2
  • Tide moves out (i.e. AA is now in dry reaction
    conditions)
  • Step 3

Likely present in primitive atmosphere
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  • N is protected as a carbamate (recall BOC)
  • CO2H activated as an anhydride

Loss of N2 is driving force for rxn
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  • Step 4 5 Condensation
  • Experimentally, this system generates
    oligo-peptides with diastereoselection
    preferred sequences (?)
  • May have given rise to earliest protein catalysts

Drives rxn
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