Peptides:
Mixture Sciences' peptide positional scanning libraries have been used in a wide range of bioassays by both pharmaceutical and academic institutions in order to identify novel enzyme inhibitors, receptor agonists and antagonists, antimicrobial, antifungal, and antiviral compounds. Below is a list of some of the libraries used in different bioassays as well as the activity of leads generated from testing those libraries.
|
Type
|
Receptor
|
Activity
of Lead Compounds
|
|
Tetrapeptide
|
Opioid
|
IC50
= 2 nM1,2, Ki =0.4 nM2
|
|
Hexapeptide
|
Opioid
|
IC50
= 17 nM3, 45 nM4
|
|
Hexapeptide
|
Antipeptide/Antibody
|
IC50
= 2 nM5
|
|
Decapeptide
|
Antipeptide/Antibody
|
IC50
= 0.6 nM6
|
|
Hexapeptide
|
Enzyme
Inhibitors
|
Ki
= 3.2 nM7, 360 nM7
|
|
Hexapeptide
|
Melittin
Inhibitors
|
Ki
= 3.0 ug/mL4
|
|
Decapeptide
|
T-cell
|
IC50
= 18 nM8
|
|
Decapeptide
|
T-cell
|
EC50
= 0.0002 u/mL9,10
|
Positional Scanning Libraries are composed of systematically arranged mixtures. In the case of single-position-defined Positional Scanning Libraries, each compound present in a given mixture has a common individual building block at a given position, while the remaining positions are composed of mixtures of all the building blocks used to prepare the library; a common single building block defines each relevant mixture.
For example a hexapeptide library can be illustrated as above, as six separate sublibraries. Sublibrary 1 contains 20 different samples. The first sample contains Alanine, represented by an A, at the first position and a mixture, represented by an X, at the other five positions. The mixture represents an equal molar amount of 19 amino acids (the 20 natural minus Cysteine). This means that Sample 1 contains a mixture of 2.4 million hexapeptides all with the first position fixed with Alanine. Sample 2 contains a mixture of 2.4 million hexapeptides all with the first position fixed with Cysteine, C. This format is continued through the length of the peptide forming the 6 sublibraries. This means that 47 million different hexapeptides can be screened using only 6 x 20 = 120 samples.
|
Type
|
#
of Compounds
|
#
of Samples
|
Amino
Terminus
|
Carboxyl
Terminus
|
|
Hexapeptide
|
47
million
|
120
|
Free
|
Free
|
|
Hexapeptide
|
47
million
|
120
|
Acetyl
|
Free
|
|
Hexapeptide
|
47
million
|
120
|
Free
|
Amide
|
|
Hexapeptide
|
47
million
|
120
|
Acetyl
|
Amide
|
|
Decapeptide
|
300
billion
|
180
|
Free
|
Free
|
|
Decapeptide
|
300
billion
|
180
|
Acetyl
|
Free
|
|
Decapeptide
|
300
billion
|
180
|
Free
|
Amide
|
|
Decapeptide
|
300
billion
|
180
|
Acetyl
|
Amide
|
|
Dodecapeptide
|
6
trillion
|
200
|
Free
|
Amide
|
|
Dodecapeptide
|
6
trillion
|
200
|
Free
|
Amide
|
|
Hexapeptide(a)
|
47
million
|
120
|
Acetyl
|
Amide
|
|
Decapeptide(a)
|
300
billion
|
180
|
Acetyl
|
Amide
|
|
Decapeptide(a)
|
300
billion
|
180
|
Free
|
Amide
|
|
Tetrapeptide(b)
|
12
million
|
240
|
Acetyl
|
Amide
|
|
Tetrapeptide(b)
|
12
million
|
240
|
Free
|
Amide
|
(a)
These libraries contain only the D versions of the natural amino acids.
(b) These libraries contain L, D and unusual amino acids.
Reference: (1) Houghten, R.A., et al. J. Med. Chem. 42:3743 1999. (2) Dooley, C.T., et al. J. Biol. Chem. 273:18848 1998. (3) Dooley, C.T., et al. Life Sci. 52:1509 1993. (4) Pinilla, C., et al. Drug. Dev. Res. 33:133 1994. (5) Pinilla, C., et al. Biotechniques 13:901 1992. (6) Pinilla, C., et al. Biochem. J. 301:847 1994. (7) Apletalina, E., et al. J. Biol. Chem. 273:26589 1998. (8) Pinilla, C., et al. Cancer Research 61:5153 2001. (9) Hemmer, B., et al. J. Immun. 12:375 2000. (10) Hemmer, B., et al. Nature Med. 5:1375 1999.
