Pepducins are cell-penetrating
peptides
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
that act as
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
modulators of signal transference from receptors to
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ac ...
s. Pepducins were first developed at the
Tufts Medical Center
Tufts Medical Center (until 2008 Tufts-New England Medical Center) in Boston, Massachusetts is a downtown Boston hospital midway between Chinatown and the Boston Theater District.
The hospital is a community based medical center for biomedical r ...
laboratories of
Dr. Athan Kuliopulos and
Dr. Lidija Covic.
Pepducins employ lipidated fragments of intracellular
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
loops to modulate GPCR action in targeted
cell-signaling pathways.
A pepducin
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
consists of a short peptide derived from a GPCR intracellular loop tethered to a
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
moiety
Moiety may refer to:
Chemistry
* Moiety (chemistry), a part or functional group of a molecule
** Moiety conservation, conservation of a subgroup in a chemical species
Anthropology
* Moiety (kinship), either of two groups into which a society is ...
. This structure allows pepducin
lipopeptide
A lipopeptide is a molecule consisting of a lipid connected to a peptide. They are able to self-assemble into different structures. Many bacteria produced these molecules as a part of their metabolism, especially those of the genus '' Bacillus'', ...
s to anchor in the
cell membrane lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vi ...
and target the GPCR/G protein interface via a unique intracellular
allosteric
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
mechanism. Pepducins for over 15 different GPCRs have been successfully produced, several of which have shown activity in preclinical ''
in vivo'' models.
An anti-
PAR4
Protease-activated receptor 4 (PAR-4), also known as coagulation factor II (thrombin) receptor-like 3, is a protein that in humans is encoded by the ''F2RL3'' gene.
Function
Coagulation factor II (thrombin) receptor-like 3 (F2RL3) is a member ...
pepducin extended bleeding time in mice and protected against systemic platelet activation and thrombosis.
[
A ]CXCR4
C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor.
Function
CXCR-4 is an alpha-chemok ...
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
pepducin mobilizes bone marrow hematopoietic cells.
A PAR1 pepducin, PZ-128, has successfully completed phase I clinical trials.
References
{{reflist
Lipopeptides