5 research outputs found
Highly <i>N</i>‑Methylated Peptides from the Antarctic Sponge <i>Inflatella coelosphaeroides</i> Are Active against <i>Plasmodium falciparum</i>
Malaria, caused by the parasite Plasmodium falciparum, continues to threaten much of the
world’s population, and
there is a pressing need for expanding treatment options. Natural
products have been a vital source of such drugs, and here we report
seven new highly N-methylated linear peptides, friomaramide
B (2) and shagamides A–F (3–8) from the marine sponge Inflatella coelosphaeroides, collected in Antarctic waters, which demonstrate activity against
three strains of blood-stage P. falciparum. The planar
structures of these metabolites were solved by interpreting NMR data,
as well as HRESIMS/MS fragmentation patterns, while Marfey’s
analysis was used to establish the configurations of the amino acids.
Reisolation of the previously reported compound friomaramide A (1) allowed us to revise its structure. The panel of isolated
compounds allowed establishing structure/activity relationships and
provided information for future structure optimization for this class
of P. falciparum inhibitory metabolites
Scavenging of Toxic Acrolein by Resveratrol and Hesperetin and Identification of Adducts
The objective of this study was to
investigate the ability of resveratrol
and hesperetin to scavenge acrolein at pH 7.4 and 37 °C. About
6.4 or 5.2% of acrolein remained after reaction with resveratrol or
hesperetin for 12 h at equimolar concentrations. An acrolein–resveratrol
adduct and two acrolein–hesperetin adducts were isolated. Their
structures were elucidated using mass and NMR spectroscopy. Acrolein
reacted with resveratrol at the C-2 and C-3 positions through nucleophilic
addition and formed an additional heterocyclic ring. Two similar monoacrolein-conjugated
adducts were identified for hesperetin. Spectroscopic data suggested
each acrolein–hesperetin adduct was a mixture of four stereoisomers
due to the existence of two chiral carbon atoms. Yield of adducts
was low at pH 5.4 but increased at pH 7.4 and 8.4. Higher pH also
promoted the formation of diacrolein adducts. Results suggest that
resveratrol and hesperetin exert health benefits in part through neutralizing
toxic acrolein in vivo
Structure–Activity Relationships of Peptides Incorporating a Bioactive Reverse-Turn Heterocycle at the Melanocortin Receptors: Identification of a 5800-fold Mouse Melanocortin‑3 Receptor (mMC3R) Selective Antagonist/Partial Agonist versus the Mouse Melanocortin‑4 Receptor (mMC4R)
The
melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors regulate
energy homeostasis, food intake, and associated physiological conditions.
The melanocortin-4 receptor (MC4R) has been studied extensively. Less
is known about specific physiological roles of the melanocortin-3
receptor (MC3R). A major obstacle to this lack of knowledge is attributed
to a limited number of identified MC3R selective ligands. We previously
reported a spatial scanning approach of a 10-membered thioether-heterocycle
ring incorporated into a chimeric peptide template that identified
a lead nM MC4R ligand. Upon the basis of those results, 17 compounds
were designed and synthesized that focused upon modification in the
pharmacophore domain. Notable results include the identification of
a 0.13 nM potent 5800-fold mMC3R selective antagonist/slight partial
agonist versus a 760 nM mMC4R full agonist (ligand <b>11</b>). Biophysical experiments (two-dimensional <sup>1</sup>H NMR and
computer-assisted molecular modeling) of this ligand resulted in the
identification of an inverse Îł-turn secondary structure in the
ligand pharmacophore domain
1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization
The melanocortin
system is involved in the regulation of complex physiological functions,
including energy and weight homeostasis, feeding behavior, inflammation,
sexual function, pigmentation, and exocrine gland function. The five
melanocortin receptors that belong to the superfamily of G protein-coupled
receptors (GPCRs) are regulated by endogenously expressed agonists
and antagonists. The aim of this study was to explore the potential
of replacing the disulfide bridge in chimeric AGRP-melanocortin peptide
Tyr-cÂ[Cys-His-d-Phe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH<sub>2</sub> (<b>1</b>) with 1,2,3-triazole moieties. A series of 1,2,3-triazole-bridged
peptidomimetics were designed, synthesized, and pharmacologically
evaluated at the mouse melanocortin receptors. The ligands possessed
nanomolar to micromolar agonist cAMP signaling potency. A key finding
was that the disulfide bond in peptide <b>1</b> can be replaced
with the monotriazole ring with minimal effect on the functional activity
at the melanocortin receptors. The 1,5-disubstituted triazole-bridged
peptide <b>6</b> showed equipotent functional activity at the
mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared
to those of <b>1</b>. Interestingly, the 1,4- and 1,5-disubstituted
isomers of the triazole ring resulted in different selectivities at
the receptor subtypes, indicating subtle structural features that
may be exploited in the generation of selective melanocortin ligands.
Introducing cyclic and acyclic bis-triazole moieties into chimeric
AGRP template <b>1</b> generally decreased agonist activity.
These results will be useful for the further design of neuronal chemical
probes for the melanocortin receptors as well as in other receptor
systems
Inhibitor-Induced Conformational Shifts and Ligand-Exchange Dynamics for HIV‑1 Protease Measured by Pulsed EPR and NMR Spectroscopy
Double electron–electron resonance (DEER) spectroscopy
was
utilized to investigate shifts in conformational sampling induced
by nine FDA-approved protease inhibitors (PIs) and a nonhydrolyzable
substrate mimic for human immunodeficiency virus type 1 protease (HIV-1
PR) subtype B, subtype C, and CRF_01 A/E. The ligand-bound subtype
C protease has broader DEER distance profiles, but trends for inhibitor-induced
conformational shifts are comparable to those previously reported
for subtype B. Ritonavir, one of the strong-binding inhibitors for
subtypes B and C, induces less of the closed conformation in CRF_01
A/E. <sup>1</sup>H–<sup>15</sup>N heteronuclear single-quantum
coherence (HSQC) spectra were acquired for each protease construct
titrated with the same set of inhibitors. NMR <sup>1</sup>H–<sup>15</sup>N HSQC titration data show that inhibitor residence time
in the protein binding pocket, inferred from resonance exchange broadening,
shifting or splitting correlates with the degree of ligand-induced
flap closure measured by DEER spectroscopy. These parallel results
show that the ligand-induced conformational shifts resulting from
protein–ligand interactions characterized by DEER spectroscopy
of HIV-1 PR obtained at the cryogenic temperature are consistent with
more physiological solution protein–ligand interactions observed
by solution NMR spectroscopy