8.3.2.1 Fish Antifreeze Proteins and Drug Design
Antifreeze proteins are a group of unique macromolecules that prevent marine bony fish
from freezing in their icy ocean habitat. This class of proteins was discovered by
DeVries of Stanford University in the early 1960s. Many types of antifreeze proteins
have been isolated and characterized from different fish. The first type is a glycoprotein
antifreeze made from a repeating tripeptide unit (Ala–Ala–Thr)nwith a disaccharide
moiety attached to the threonyl residue. Next, there are three antifreeze protein (AFP)
macromolecules: type I is an alanine-rich, amphiphilic α-helix; Type II is a protein with
five disulfide bridges and a secondary structure characterized by numerous reverse
β-turns; Type III is composed of a variety of different proteins of varying length and
516 MEDICINAL CHEMISTRY
Figure 8.7 Top: Sequence of Aβ1–43 and sites of secretase cleavage. γ-Secretase has low
specificity, cleaving the amyloid precursor protein (APP) anywhere between residues 39 to 43 of
Aβ. The transmembrane portion of APP is indicated. Bottom: processing of amyloid precursor
protein (APP): (A) “Normal” cleavage within Aβregion by α-secretase; (B) pathogenic cleavage
of APP by β- and γ-secretase, liberating Aβ, which can become incorporated into growing plaques.
(Note: Aβ=β-Amyloid Peptide)