Peptides quantitative structure-function relationships: an automated mutation strategy to design peptides and pseudopeptides from substitution matrices.
The process by which analogs in peptide chemistry are currently designed does not include any quantitative basis for amino acid substitutions from pharmacological leads. Here, we show that substitution matrices such as PAM 250 can provide quantitative constraints compatible with biological activity. This article describes its use in a strategy of rational amino acid substitution in peptides and proteins: we have computed a chemically derived matrix equivalent to the well-known PAM 250 matrix, reflecting the natural mutability rates of amino acids in protein evolutions but that can be extended to all the noncoded amino acids. Some of these noncoded amino acids are widely used to mimic secondary structure, to constrain backbone conformation, or to evade protease degradation. An automated sequence mutation (ASM) strategy has been defined to generate mutations within constraints. Application of such a substitution matrix to quantitative structure-function relationship studies will be of use in the design of proteins and peptides destined to become pharmaceutical drugs. In particular, issues such as which functionally conserved substitutions are able to satisfy conformational restrictions, oral bioavailability, or formulation demands can be quantitatively addressed.
Adenot
M
M
Centre de Biochimie Structurale, CNRS UMR 9955, INSERM U 414, Faculté de Pharmacie 15, Montpellier, France.
Sarrauste de Menthière
C
C
Chavanieu
A
A
Calas
B
B
Grassy
G
G
D019943:Amino Acid Substitution; D000818:Animals; D001331:Automation; D019332:Endothelin-1 / Q000031:analogs & derivatives / Q000737:chemistry* / Q000235:genetics; D016296:Mutagenesis; D009842:Oligopeptides / Q000737:chemistry; D010121:Oxytocin / Q000737:chemistry* / Q000235:genetics; D010455:Peptides / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine
D019332:Endothelin-1; D009842:Oligopeptides; D010455:Peptides; D010121:Oxytocin