TY - CHAP
T1 - Rational design strategies for developing synthetic inhibitors of helical protein interfaces
AU - Mahon, Andrew B.
AU - Miller, Stephen E.
AU - Joy, Stephen T.
AU - Arora, Paramjit S.
N1 - Funding Information:
We thank the National Institutes of Health (GM073943) and National Science Foundation (CHE 0848410) for financial support.
PY - 2012
Y1 - 2012
N2 - Cellular function depends on highly specific interactions between biomolecules (proteins, RNA, DNA, and carbohydrates). A basic limitation of drug development is the inability of traditional "small-molecule" pharmaceuticals to specifically target large protein interfaces, many of which are desirable drug targets. α-Helices, ubiquitous elements of protein structures, play fundamental roles in many protein-protein interactions. Stable mimics of α-helices that can predictably disrupt these interactions would be invaluable as tools in molecular biology, and as leads in drug discovery. The past decade has seen exciting progress in the molecular design of these protein domain mimetics and their remarkable potential to inhibit challenging interactions. Key challenges in the field include identification of suitable targets and bioavailability of medium-sized molecules, which do not conform to empirical rules followed in traditional drug design. Stabilized α-helices bypass some of the strict limitations that have been placed on drug discovery. When designing potential drug candidates, medicinal chemists often adhere to the Lipinski rules, which stipulate that the molecular mass of a drug should not exceed 500 Da. Recent findings suggest that large synthetic α-helices can traffic into the cell and efficiently compete with cellular protein-protein interactions, contrary to predictions based on the Lipinski rules. Although these molecules have undoubtedly proven their value as probes for decoding biological complexity, the next big question is whether these molecules can become therapeutics. This chapter discusses the properties of protein-protein interactions, emerging rules for identifying protein targets and design criteria guiding construction of helix mimetics.
AB - Cellular function depends on highly specific interactions between biomolecules (proteins, RNA, DNA, and carbohydrates). A basic limitation of drug development is the inability of traditional "small-molecule" pharmaceuticals to specifically target large protein interfaces, many of which are desirable drug targets. α-Helices, ubiquitous elements of protein structures, play fundamental roles in many protein-protein interactions. Stable mimics of α-helices that can predictably disrupt these interactions would be invaluable as tools in molecular biology, and as leads in drug discovery. The past decade has seen exciting progress in the molecular design of these protein domain mimetics and their remarkable potential to inhibit challenging interactions. Key challenges in the field include identification of suitable targets and bioavailability of medium-sized molecules, which do not conform to empirical rules followed in traditional drug design. Stabilized α-helices bypass some of the strict limitations that have been placed on drug discovery. When designing potential drug candidates, medicinal chemists often adhere to the Lipinski rules, which stipulate that the molecular mass of a drug should not exceed 500 Da. Recent findings suggest that large synthetic α-helices can traffic into the cell and efficiently compete with cellular protein-protein interactions, contrary to predictions based on the Lipinski rules. Although these molecules have undoubtedly proven their value as probes for decoding biological complexity, the next big question is whether these molecules can become therapeutics. This chapter discusses the properties of protein-protein interactions, emerging rules for identifying protein targets and design criteria guiding construction of helix mimetics.
KW - Helix mimetics
KW - Inhibitors
KW - Protein-protein interactions
UR - http://www.scopus.com/inward/record.url?scp=84864049238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864049238&partnerID=8YFLogxK
U2 - 10.1007/978-3-642-28965-1_6
DO - 10.1007/978-3-642-28965-1_6
M3 - Chapter
AN - SCOPUS:84864049238
SN - 9783642289644
T3 - Topics in Medicinal Chemistry
SP - 197
EP - 230
BT - Protein-protein interactions
A2 - Wendt, MD
PB - Springer
ER -