Recombinant proteins are
important therapeutics due to potent, highly specific, and nontoxic actions in
vivo. However, they are expensive medicines to manufacture, chemically
unstable, and difficult to administer with low patient uptake and compliance.
Small molecule drugs are cheaper and more bioavailable, but less
target-specific in vivo and often have associated side effects. Here we combine
some advantages of proteins and small molecules by taking short amino acid
sequences that confer potency and selectivity to proteins, and fixing them as
small constrained molecules that are chemically and structurally stable and
easy to make. We show that short peptides, corresponding to helical epitopes
from viral, bacterial, or human proteins, can be strategically fixed in highly a-helical
structures in water. These helix-constrained compounds have similar biological
potencies as proteins that bear the same helical sequences. Examples are (i) a
picomolar inhibitor of Respiratory Syncytial Virus F protein mediated fusion
with host cells, (ii) a nanomolar inhibitor of RNA binding to the transporter
protein HIV-Rev, (iii) a submicromolar inhibitor of Streptococcus pneumoniae
growth induced by quorum sensing pheromone Competence Stimulating Peptide, and
(iv) a picomolar agonist of the GPCR pain receptor opioid receptor like
receptor ORL-1. (vi) Agonists of AP-1 transciptional regulator This approach
can be generally applicable to downsizing helical1 regions of proteins with
broad applications to biology and medicine
- Harrison, R. S.; Shepherd, N. E.; Hoang, H. N.; Ruiz-Gómez, G.; Hill, T. A.; Driver, R. W.; Desai, V. S.; Young, P. R.; Abbenante, G.; Fairlie, D. P. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 11686-11691.