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Printable Handouts
Navigable Slide Index
- Introduction
- Proteins: connecting chemistry and life
- Many of them cannot be obtained biologically
- How to make biologically unattainable proteins? Chemistry
- Beginning
- Synthesis of peptides and small proteins
- Solid-phase peptide synthesis
- Synthetic ribonuclease A (124 aa)
- Peptide segment condensation
- Synthetic Aequorea green fluorescent protein (238 aa)
- Challenges for protected-peptide condensation
- Chemoselective peptide ligation
- Native Chemical Ligation (NCL)
- Chemical synthesis of polymer-modified erythropoietin
- NCL combined with desulfurization
- Free radical-based desulfurization of cysteine
- NCL using mercapto-amino acids
- Auxiliary-mediated ligation
- Thioester synthesis
- Thioester equivalents
- Hydrazide-based protein ligation
- Chemical synthesis of peptide hydrazides
- Sequential synthesis using hydrazides
- Convergent synthesis using hydrazides
- Compatible with almost all modifications
- Serine/threonine ligation
- Ketoacid-hydroxylamine ligation
- Protein semisynthesis
- Recombinant N-cysteinyl protein
- Recombinant protein a-thioester
- Recombinant protein hydrazides
- Enzyme-mediated peptide ligation
- Can we synthesize the whole human proteome?
- Challenge 1: solubility
- Challenge 2: folding
- “Temporary structural supports”
- Removable backbone modification (RBM)
- Example: GPCR fragment
- Synthesis of Kir5.1
- Removable glycosylation modification (RGM)
- Installation of glycosylation
- Synthesis of human interleukin-5
- Glycosylation-assisted folding
- Removal of glycosylation by O-GlcNAcase
- Challenge 3: ligation between large segments
- Reductive diselenide-selenoester ligation (rDSL)
- Synthesis of a lipidated protein
- Proximity-driven protein synthesis
- Backbone-installed split intein-assisted ligation (BISIAL)
- BISIAL at µM concentrations
- Synthesis of membrane-associated D-proteins
- Applications of chemical protein synthesis
- N-degron pathway E3: Ubr1
- How does Ubr1 work?
- Chemical trapping
- Chemical protein synthesis (not accessible biologically)
- Complex formation visualized by Cryo-EM
- Chemical secret of Ubr1-mediated polyubiquitination
- In vivo validation
- Mirror-image peptide/protein drugs
- Mirror-image phage display
- D-peptide targeting immune checkpoint PD-L1
- Chemical synthesis of DPD-L1 (not accessible biologically)
- Identification of D-peptides targeting PD-L1
- DPPA-1 inhibits tumor growth
- D-peptide targeting immune checkpoint TIGIT
- Chemical synthesis of DIgVTIGIT (not accessible biologically)
- Identification of D-peptides targeting TIGIT
- Characterization of D-peptide inhibitors of TIGIT
- Characterization of D-peptide inhibitors of TIGIT
- Summary (1)
- Summary (2)
Topics Covered
- Synthesis of peptides and small proteins
- Chemical synthesis
- Native Chemical Ligation
- Enzyme-mediated peptide ligation
- Backbone-installed split intein-assisted ligation (BISIAL)
- Chemical trapping
- Mirror-image peptide/protein drugs
Talk Citation
Liu, L. (2024, April 30). Chemical synthesis of proteins [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 12, 2024, from https://doi.org/10.69645/NJKV1300.Export Citation (RIS)
Publication History
Financial Disclosures
- There are no commercial/financial matters to disclose.
A selection of talks on Methods
Transcript
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0:00
Dear listeners, my
name is Lei Liu.
I come from Tsinghua
University in Beijing.
Today I'm glad to share with you
the Chemical Synthesis
of Proteins.
0:12
First, we need to emphasize
that proteins are
large organic molecules that
connect chemistry to life.
Proteins are important
for understanding
how life works at
the molecular level.
Proteins are also increasingly
being developed as drugs.
In addition, proteins
are receiving
increasing attention in
the development of
advanced materials.
0:37
Proteins are usually produced
by genetic recombination
techniques.
However, there are many proteins
that cannot be
obtained biologically.
This includes proteins with
complex post-translational
modifications,
proteins with unnatural
functional motifs,
and proteins composed entirely
of mirror-image D-amino acids.
1:02
Our central question
is how to generate
proteins that are not
biologically available.
The way to achieve this
goal is chemistry.
In retrosynthetic
thinking, we can achieve
our goal through a
divide-and-conquer strategy.
First, we need to produce
the building blocks of our
targeted proteins which
we call protein segments, by
total chemical synthesis
or recombinant expression.
Then, we need to assemble
these protein segments through
chemical transformations
to produce
correctly folded
targeted proteins.
1:39
Going back to the origins of
chemical protein synthesis, at
the beginning of
the 20th century,
Emil Fischer and his
contemporary chemists
came up with the idea of making
enzymes through
synthetic chemistry.
At that time, synthesizing
even a small peptide was
a significant challenge.