Browse
Submit Data
Databases
API
Help

Dataset Information

4 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.

ABSTRACT: Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

SUBMITTER: Bai B

PROVIDER: S-EPMC8291138 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors.

Project description:Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate in vitro SARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. This effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease.

| S-EPMC8529539 | biostudies-literature

Distinct Palladium(II) Carbene Complexes Supported by Six-Membered 1,3-Disubstituted Permidin-2-ylidene, Six-Membered N-Heterocyclic Carbenes.

Project description:The first synthesis, isolation, and characterization of permidin-2-ylidene complexes of Pd(II) is reported with entry resulting from either a direct reaction with isolable six-membered N-heterocyclic carbene or from the enetetramine, arising from dimerization of the carbene. Furthermore, a simplified method to prepare N,N'-disubstituted perimidinium bromide salts, precursors to 1,3-disubstituted perimidin-2-ylidene, was achieved using ammonium bromide as a source of weak acid. Through synthesis and nuclear magnetic resonance spectroscopic analysis of a carbene-phosphinidine adduct, an interrogation of the fundamental π-bonding ability of 1,3-diisopropylperimidin-2-ylidene revealed this interaction to be weak and of a similar order to unsaturated imidazol-2-ylidenes.

| S-EPMC6644826 | biostudies-literature

Seven-Membered Lactam Derivatives of Podophyllotoxins as New Pesticidal Agents.

Project description:As a continuation of our efforts to discover and develop natural-product-based insecticidal agents, three novel and unusual 7-membered lactam derivatives of podophyllotoxin were prepared by thionyl chloride-mediated ring-expanded Beckmann rearrangement. The steric configurations of 3a-c were unambiguously identified by X-ray crystallography. It demonstrated that the configuration of the picropodophyllotoxin C4-oximes could also be confirmed by the corresponding C-ring expansion products via Beckmann rearrangement. Moreover, it was obviously further testified that when picropodophyllones reacted with hydroxylamine hydrochloride, only E configuration of picropodophyllotoxin C4-oximes was selectively produced. Compounds 3b and 3c showed more potent pesticidal activity than toosendanin against oriental armyworm, Mythimna separata (Walker).

| S-EPMC5478614 | biostudies-literature

Six-membered-ring inorganic materials: definition and prospects.

Project description:The six-membered ring (SMR) is a common structure unit for numerous material systems. These materials include, but are not limited to, the typical two-dimensional materials such as graphene, h-BN, and transition metal dichalcogenides, as well as three-dimensional materials such as beryllium, magnesium, MgB2 and Bi2Se3. Although many of these materials have already become 'stars' in materials science and condensed-matter physics, little attention has been paid to the roles of the SMR unit across a wide range of compositions and structures. In this article, we systematically analyze these materials with respect to their very basic SMR structural unit, which has been found to play a deterministic role in the occurrence of many intriguing properties and phenomena, such as Dirac electronic and phononic spectra, superconductivity and topology. As a result, we have defined this group of materials as SMR inorganic materials, opening up a new perspective on materials research and development. With their unique properties, SMR materials deserve wide attention and in-depth investigation from materials design, new physical discoveries to target-wizard applications. It is expected that SMR materials will find niche applications in next-generation information technology, renewable energy, space, etc.

| S-EPMC8294346 | biostudies-literature

Improved Synthesis of a Cyclic Glutamine Analogue Used in Antiviral Agents Targeting 3C and 3CL Proteases Including SARS-CoV-2 M<sup>pro</sup>.

Project description:An intermediate in the synthesis of numerous antiviral protease inhibitors is the glutamine analogue, (3S)-pyrrolid-2-one-3-yl-l-alanine. Preparations of compounds based on this pharmacophore are hindered by the lack of a reliably high yielding synthesis of protected forms of this amino acid. We describe an improved scalable route with readily available reagents and facile purification. This methodology employs γ-allylation of dimethyl N-BocGlu, further Boc N-protection, OsO4-periodate oxidation, O-Me oxime formation, and RaNi-catalyzed hydrogenolysis with concomitant cyclization under basic conditions.

| S-EPMC8425337 | biostudies-literature

Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.

Project description:Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1' 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with K i-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2-P1'. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1' 4-(trifluoromethyl)phenyl side chain.

| S-EPMC4027635 | biostudies-literature

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity.

Project description:The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic candidates, particularly for combating newly emergent viral threats. The innate immune system features a sustained capability to combat pathogens through production of antimicrobial peptides (AMPs); however, these AMPs have shortcomings that can preclude clinical use. The essential functional features of AMPs have been recapitulated by peptidomimetic oligomers, yielding effective antibacterial and antifungal agents. Here, we show that a family of AMP mimetics, called peptoids, exhibit direct antiviral activity against an array of enveloped viruses, including the key human pathogens Zika, Rift Valley fever, and chikungunya viruses. These data suggest that the activities of peptoids include engagement and disruption of viral membrane constituents. To investigate how these peptoids target lipid membranes, we used liposome leakage assays to measure membrane disruption. We found that liposomes containing phosphatidylserine (PS) were markedly sensitive to peptoid treatment; in contrast, liposomes formed exclusively with phosphatidylcholine (PC) showed no sensitivity. In addition, chikungunya virus containing elevated envelope PS was more susceptible to peptoid-mediated inactivation. These results indicate that peptoids mimicking the physicochemical characteristics of AMPs act through a membrane-specific mechanism, most likely through preferential interactions with PS. We provide the first evidence for the engagement of distinct viral envelope lipid constituents, establishing an avenue for specificity that may enable the development of a new family of therapeutics capable of averting the rapid development of resistance.

| S-EPMC10425984 | biostudies-literature

Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor.

Project description:A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CLpro, but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CLpro when combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CLpro but also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.

| S-EPMC7126642 | biostudies-literature

C(alkenyl)-H Activation via Six-Membered Palladacycles: Catalytic 1,3-Diene Synthesis.

Project description:A catalytic method to prepare highly substituted 1,3-dienes from two different alkenes is described using a directed, palladium(II)-mediated C(alkenyl)-H activation strategy. The transformation exhibits broad scope across three synthetically useful substrate classes masked with suitable bidentate auxiliaries (4-pentenoic acids, allylic alcohols, and bishomoallylic amines) and tolerates internal nonconjugated alkenes, which have traditionally been a challenging class of substrates in this type of chemistry. Catalytic turnover is enabled by either MnO2 as the stoichiometric oxidant or co-catalytic Co(OAc)2 and O2 (1 atm). Experimental and computational studies were performed to elucidate the preference for C(alkenyl)-H activation over other potential pathways. As part of this effort, a structurally unique alkenylpalladium(II) dimer was isolated and characterized.

| S-EPMC6089246 | biostudies-literature

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators.

Project description:It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer's disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with KAs ranging between 3.46 and 80.5 ?M, whereas they were not active towards hCA II (KAs > 100 ?M). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed KAs towards hCA VII in the nanomolar range after evaluation by a CO? hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site.

| S-EPMC6149746 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data