Full Sequence Amino Acid Scanning of θ-Defensin RTD-1 Yields a Potent Anthrax Lethal Factor Protease Inhibitor.
θ-Defensin RTD-1 is a noncompetitive inhibitor of anthrax lethal factor (LF) protease (IC50= 390 ± 20 nM, Ki= 365 ± 20 nM) and a weak inhibitor of other mammalian metalloproteases such as TNFα converting enzyme (TACE) (Ki= 4.45 ± 0.48 μM). Using full sequence amino acid scanning in combination with a highly efficient "one-pot" cyclization-folding approach, we obtained an RTD-1-based peptide that was around 10 times more active than wild-type RTD-1 in inhibiting LF protease (IC50= 43 ± 3 nM, Ki= 18 ± 1 nM). The most active peptide was completely symmetrical, rich in Arg and Trp residues, and able to adopt a native RTD-1-like structure. These results show the power of optimized chemical peptide synthesis approaches for the efficient production of libraries of disulfide-rich backbone-cyclized peptides to quickly perform structure-activity relationship studies for optimizing protease inhibitors.
Yilong
Y
Li
Andrew
A
Gould
Teshome
T
Aboye
Tao
T
Bi
Department of Chemistry, State University of New York , Albany, New York 12222, United States.
Leonard
L
Breindel
Department of Chemistry, State University of New York , Albany, New York 12222, United States.
Alexander
A
Shekhtman
Julio A
0000-0001-9150-0665
JA
Camarero
D000596:Amino Acids / Q000737:chemistry*; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D003500:Cyclization; D023082:Defensins / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology
D000596:Amino Acids; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D023082:Defensins; D011480:Protease Inhibitors; C030325:anthrax toxin; C450142:theta-defensin