Title: A real example:
1 A real example
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4Natural Product Peptides, Peptidomimetics
Peptide Analogues
- Natural Product Peptides (nonribosomal
peptides) - Product of secondary metabolism
- Synthesized on the NRPS
- Numerous pharmaceutically relevant peptides
5More Nonribosomal Peptides
6- 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
7Peptide 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
8AMP 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)
9Teflon? 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
10magainin series sites of fluorination Leu 6,
Ala 9, Gly 13, Val 17, and Ile 20
NMR structure of magainin 2
Other Analogues
11Peptidomimetics
- 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
12Examples of Peptidomimetics
Mimic ?-sheets
13Peptide 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
14Peptide 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
15- 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
16Experiment (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
17Other 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!
18- 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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20- Step 2
- Tide moves out (i.e. AA is now in dry reaction
conditions) - Step 3
Likely present in primitive atmosphere
21- N is protected as a carbamate (recall BOC)
- CO2H activated as an anhydride
Loss of N2 is driving force for rxn
22- Step 4 5 Condensation
- Experimentally, this system generates
oligo-peptides with diastereoselection
preferred sequences (?) - May have given rise to earliest protein catalysts
Drives rxn