Identification and characterization of folding inhibitors of hen egg lysozyme: an example of a new paradigm of drug design.
Studies of protein folding indicate the presence of native contacts in the denatured state, giving rise to folding elements which contribute to the accomplishment of the native state. The possibility of finding molecules which can interact with specific folding elements of a target protein preventing it from reaching its native state, and hence from becoming biologically active, is particularly attractive. The notion that folding elements not only provide molecular recognition directing the folding process, but also have conserved sequence, implies that targeting such elements will make protein folding inhibitors less susceptible to mutations which, in many cases, abrogate drug effects. The folding-inhibition strategy can lead to a truly novel and rational approach to drug design, aside from providing new insight into folding. This is illustrated in the case of hen egg lysozyme.
Caldarini
M
M
Department of Physics, University of Milano and INFN, via Celoria 16, 20133 Milano, Italy.
Vasile
F
F
Provasi
D
D
Longhi
R
R
Tiana
G
G
Broglia
R A
RA
D000818:Animals; D002645:Chickens; D015195:Drug Design; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D009113:Muramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013053:Spectrophotometry
D010455:Peptides; C421864:hen egg lysozyme; D009113:Muramidase