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Protein Chemical Synthesis in Drug Discovery

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Protein Ligation and Total Synthesis I

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 362))

Abstract

The discovery of novel therapeutics to combat human disease has traditionally been among the most important goals of research chemists. After a century of innovation, state-of-the-art chemical protein synthesis is now capable of efficiently assembling proteins of up to several hundred residues in length from individual amino acids. By virtue of its unique ability to incorporate non-native structural elements, chemical protein synthesis has been seminal in the recent development of several novel drug discovery technologies. In this chapter, we review the key advances in peptide and protein chemistry which have enabled our current synthetic capabilities. We also discuss the synthesis of d-proteins and their applications in mirror image phage-display and racemic protein crystallography, the synthesis of enzymes for structure-based drug discovery, and the direct synthesis of homogenous protein pharmaceuticals.

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Abbreviations

AAA:

Amino acid analysis

Acm:

Acetamidomethyl

BAL:

Backbone amide linker

BHA:

Benzhydrylamine

Boc:

tert-Butyloxycarbonyl group

Bpoc:

Biphenylisopropoxycarbonyl

Bzl:

Benzyl

CBD:

Chitin-binding domain

Cbz:

Carboxybenzyl or benzyloxycarbonyl

CTC:

2-Chlorotrityl chloride

DBU:

1,8-Diazabicyclo[5. 4. 0]undec-7-ene

DCC:

N,N′-Dicyclohexylcarbodiimide

DIEA:

N,N-Diisopropylethylamine

DMF:

N,N-Dimethylformamide

DMSO:

Dimethyl sulfoxide

EPL:

Expressed protein ligation

EPO:

Erythropoietin

ESI:

Electrospray ionization

FAB:

Fast atom bombardment

Fmoc:

9-Fluorenylmethoxycarbonyl group

GCSF:

Granulocyte-colony stimulating factor

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HF:

Hydrogen fluoride

HIV-PT:

Human immunodeficiency virus-protease

HMPA:

4-Hydroxymethylphenoxyacetic acid

HMPB:

4-Hydroxymethyl-3-methoxyphenoxybutyric acid

HOBt:

1-Hydroxylbenzotriazole

HOOBt:

3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine

HPLC:

High-performance liquid chromatography

ivDde:

1-(4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl

KCL:

Kinetically controlled ligation

MALDI:

Matrix-assisted laser desorption/ionization

MBHA:

4-Methylbenzhydrylamine

MESNa:

Sodium 2-mercaptoethanesulfonate

MIPD:

Mirror image phage-display

MPAA:

4-Mercaptophenylacetic acid

MS:

Mass spectrometry

NCL:

Native chemical ligation

NHS:

N-Hydroxysuccinimide

NMP:

N-Methyl-2-pyrrolidone

NMR:

Nuclear magnetic resonance

PAL:

Peptide amide linker

PAM:

4-Hydroxymethyl-phenylacetamidomethyl

PEG:

Polyethylene glycol

rDNA:

Recombinant DNA

RP:

Reverse-phase

RSV:

Raus-sarcoma virus

SAR:

Structure-activity relationship

SPPS:

Solid-phase peptide synthesis

tBu:

tert-Butyl

TCEP:

Tris(2-carboxyethyl)phosphine

TFA:

Trifluoroacetic acid

TFET:

Trifluoroethanethiol

Thz:

1,3-Thiazolidine-4-carboxylic acid

TPO:

Thrombopoetin

VEGF:

Vascular endothelial growth factor

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Acknowledgement

The authors wish to thank Prof. Stephen B. H. Kent of the University of Chicago for his helpful comments and suggestions during the preparation of this manuscript.

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    Fa Liu & John P. Mayer

  2. Department of Chemistry, Indiana University, 800 E. Kirkwood Ave., Bloomington, IN, 47405, USA

    John P. Mayer

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    Lei Liu

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Liu, F., Mayer, J.P. (2014). Protein Chemical Synthesis in Drug Discovery. In: Liu, L. (eds) Protein Ligation and Total Synthesis I. Topics in Current Chemistry, vol 362. Springer, Cham. https://doi.org/10.1007/128_2014_598

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