3 research outputs found
Structure-Guided Chemical Optimization of Bicyclic Peptide (<i>Bicycle</i>) Inhibitors of Angiotensin-Converting Enzyme 2
Angiotensin-converting enzyme 2 (ACE2) is a metalloprotease
that
cleaves angiotensin II, a peptide substrate involved in the regulation
of hypertension. Here, we identified a series of constrained bicyclic
peptides, Bicycle, inhibitors of human ACE2 by panning
highly diverse bacteriophage display libraries. These were used to
generate X-ray crystal structures which were used to inform the design
of additional Bicycles with increased affinity and
inhibition of ACE2 enzymatic activity. This novel structural class
of ACE2 inhibitors is among the most potent ACE2 inhibitors yet described
in vitro, representing a valuable tool to further
probe ACE2 function and for potential therapeutic utility
Structure-Guided Chemical Optimization of Bicyclic Peptide (<i>Bicycle</i>) Inhibitors of Angiotensin-Converting Enzyme 2
Angiotensin-converting enzyme 2 (ACE2) is a metalloprotease
that
cleaves angiotensin II, a peptide substrate involved in the regulation
of hypertension. Here, we identified a series of constrained bicyclic
peptides, Bicycle, inhibitors of human ACE2 by panning
highly diverse bacteriophage display libraries. These were used to
generate X-ray crystal structures which were used to inform the design
of additional Bicycles with increased affinity and
inhibition of ACE2 enzymatic activity. This novel structural class
of ACE2 inhibitors is among the most potent ACE2 inhibitors yet described
in vitro, representing a valuable tool to further
probe ACE2 function and for potential therapeutic utility
Discovery of BT8009: A Nectin‑4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer
Bicycle toxin conjugates
(BTCs) are a promising new class
of molecules
for targeted delivery of toxin payloads into tumors. Herein we describe
the discovery of BT8009, a Nectin-4 targeting BTC currently under
clinical evaluation. Nectin-4 is overexpressed in multiple tumor types
and is a clinically validated target for selective delivery of cytotoxic
payloads. A Nectin-4 targeting bicyclic peptide was identified by
phage display, which showed highly selective binding for Nectin-4
but suffered from low plasma stability and poor physicochemical properties.
Multiparameter chemical optimization involving introduction of non-natural
amino acids resulted in a lead Bicycle that demonstrated high affinity
for Nectin-4, good stability in biological matrices, and a much-improved
physicochemical profile. The optimized Bicycle was conjugated to the
cytotoxin Monomethyl auristatin E via a cleavable linker to give the
targeted drug conjugate BT8009, which demonstrates potent anticancer
activity in in vivo rodent models