In This Issue
Cite This: ACS Chem. Biol. 2019, 14, 2329−2330 pubs.acs.org/acschemicalbiology
■ NEW TOOLS FOR THE CASPASE CAPER
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Caspases are the proteolytic enzymes best known for their role
in programmed cell death, or apoptosis. Humans express a
dozen caspase family members, and a variety of genetic and
chemical tools have been used to tease apart their individual
functions. While genetic perturbations come with specificity
for a particular caspase, most of the chemical inhibitors that
prevent apoptosis act more broadly, affecting the activity of
several family members at once.
In this issue, Solania et al. (DOI: 10.1021/acschem-
bio.9b00564) unveil a new cell-permeable inhibitor that is
selective for one of the executioners, casp-3. In a previous
study, a five-residue peptide sequence containing non-natural
amino acids showed promise for casp-3 selectivity but
functioned only as a probe since it was not protective in the
face of apoptosis cues. Here, replacement of one position with
a new pentofluorophenylalanine group dramatically improves
the binding kinetics to casp-3 while maintaining a high degree
of selectivity. The cocrystal structures with casp-3 and the
related protein casp-7 help elucidate the mechanism of
selectivity, while cell culture experiments demonstrate it to
be an effective inhibitor of apoptosis.
■ HIV-PROTEASE: MUTATIONAL PATHS TO DRUG
RESISTANCE
In HIV-1 protease, an enzyme key to viral replication, almost
half of its 99 amino acids can be mutated and retain catalytic
activity. As the protease gene gains individual or multiple
mutations, resistance to approved protease inhibitor drugs can
arise. Often, determining the individual or compound
mutations harbored by drug resistant viral strains helps to
understand the mechanism of resistance. While amino acid
© 2019 American Chemical Society
substitutions close to the drug-binding site or enzyme active
site are more straightforward to interpret, mutations far from
these zones in three-dimensional space are often more
puzzling.
In this issue, Henes et al. (DOI: 10.1021/acschem-
bio.9b00370) passage cells under the pressure of the approved
protease inhibitor, darunavir (DRV), and isolate drug-resistant
proteases with up to 11 mutations. With 11 mutations spread
throughout the structure, a catalytically active protease remains
but has lost its affinity for DRV by 150 000-fold. The
researchers systematically test enzymes carrying 1 to 11
mutations along with DRV by a combination of enzymology,
X-ray crystallography, and molecular dynamics simulations.
Together, the data show that multiple mutations can have
interdependent effects, and distal mutations can significantly
alter the dynamics of the protein.
■ FROM SUBSTRATES TO INHIBITORS OF LON
PROTEASE
The Lon proteases are an ATP-dependent family of serine
proteases found in all kingdoms of life. In bacteria, Lon is
important for stress responses including heat shock, phage
infection, and DNA damage. Without a functional Lon
enzyme, many normally infectious strains are no longer
capable of infecting rodent models. This makes Lon activity
a compelling target for antimicrobial compounds, either for
research studies aimed at teasing apart its multiple functions or
as potential therapeutics.
In this issue, Babin et al. (DOI: 10.1021/acschem-
bio.9b00529) test a diverse library of tetrapeptides with the
phenylalanine next to an intended cleavage site fixed, but with
the next two positions varied with one of 121 natural or
nonnatural amino acids. After determining the kinetic
parameters for many of the identified Lon substrates, the
researchers also check for selectivity by comparison to the
human proteasome. One selective peptide which displays a low
KM for the active site is then chosen as a scaffold for a new
inhibitor drug acting on Lon. A cell permeable drug, 11, is
synthesized from this peptide backbone but armed with a
boronic acid electrophile. Assays with E. coli show that
Published: November 15, 2019
2329 DOI: 10.1021/acschembio.9b00881
ACS Chem. Biol. 2019, 14, 2329−2330
ACS Chemical Biology In This Issue

treatment with this drug results in many of the phenotypes

seen by lon mutant or deleted strains.

2330 DOI: 10.1021/acschembio.9b00881

ACS Chem. Biol. 2019, 14, 2329−2330