Modulators of protein-protein interactions as antimicrobial agents.
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ABSTRACT:
SUBMITTER: Kahan R
PROVIDER: S-EPMC8341153 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein-protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.
| S-EPMC5949722 | biostudies-literature
Project description:Protein-protein interactions (PPIs) are ubiquitous in biological systems and often misregulated in disease. As such, specific PPI modulators are desirable to unravel complex PPI pathways and expand the number of druggable targets available for therapeutic intervention. However, the large size and relative flatness of PPI interfaces make them challenging molecular targets. This Account describes our systematic approach using secondary and tertiary protein domain mimics (PDMs) to specifically modulate PPIs. Our strategy focuses on mimicry of regular secondary and tertiary structure elements from one of the PPI partners to inspire rational PDM design. We have compiled three databases (HIPPDB, SIPPDB, and DIPPDB) of secondary and tertiary structures at PPI interfaces to guide our designs and better understand the energetics of PPI secondary and tertiary structures. Our efforts have focused on three of the most common secondary and tertiary structures: α-helices, β-strands, and helix dimers (e.g., coiled coils). To mimic α-helices, we designed the hydrogen bond surrogate (HBS) as an isosteric PDM and the oligooxopiperazine helix mimetic (OHM) as a topographical PDM. The nucleus of the HBS approach is a peptide macrocycle in which the N-terminal i, i + 4 main-chain hydrogen bond is replaced with a covalent carbon-carbon bond. In mimicking a main-chain hydrogen bond, the HBS approach stabilizes the α-helical conformation while leaving all helical faces available for functionalization to tune binding affinity and specificity. The OHM approach, in contrast, envisions a tetrapeptide to mimic one face of a two-turn helix. We anticipated that placement of ethylene bridges between adjacent amides constrains the tetrapeptide backbone to mimic the i, i + 4, and i + 7 side chains on one face of an α-helix. For β-strands, we developed triazolamers, a topographical PDM where the peptide bonds are replaced by triazoles. The triazoles simultaneously stabilize the extended, zigzag conformation of β-strands and transform an otherwise ideal protease substrate into a stable molecule by replacement of the peptide bonds. We turned to a salt bridge surrogate (SBS) approach as a means for stabilizing very short helix dimers. As with the HBS approach, the SBS strategy replaces a noncovalent interaction with a covalent bond. Specifically, we used a bis-triazole linkage that mimics a salt bridge interaction to drive helix association and folding. Using this approach, we were able to stabilize helix dimers that are less than half of the length required to form a coiled coil from two independent strands. In addition to demonstrating the stabilization of desired structures, we have also shown that our designed PDMs specifically modulate target PPIs in vitro and in vivo. Examples of PPIs successfully targeted include HIF1α/p300, p53/MDM2, Bcl-xL/Bak, Ras/Sos, and HIV gp41. The PPI databases and designed PDMs created in these studies will aid development of a versatile set of molecules to probe complex PPI functions and, potentially, PPI-based therapeutics.
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Project description:The use of nanomaterials alone or in composites with proteins is a promising alternative to inhibit pathogenic bacteria. In this regard, this study used seed proteins from both fenugreek (Trigonella foenum-graecum L.) (FNP) and mung bean (Viga radiate) (MNP), with silver nanoparticles (Ag-NPs) and nanocomposites of either Ag-NPs plus FNP (Ag-FNP) or Ag-NPs plus MNP (Ag-MNP) as inhibitory agents against pathogenic bacteria. FNP and MNP were isolated from fenugreek seeds and mung bean seeds, respectively, and fractionated using Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE). Both FNP and MNP were immobilized with Ag-NPs to synthesize the nanocomposites Ag-FNP and Ag-MNP, respectively. The physicochemical characteristics of Ag-NPs and their composites with proteins were studied by X-ray Diffraction (XRD), dynamic light scattering (DLS), the zeta potential, Scanning and Transmission Electron Microscopy (SEM and TEM, respectively), Atomic Force Microscopy (AFM), and the Brunauer-Emmett-Teller isotherm (BET), elucidating their structural parameters, size distribution, size charges, size surface morphology, particle shape, dimensional forms of particles, and specific surface area, respectively. The sole proteins, Ag-NPs, and their nanocomposites inhibited pathogenic Gram-positive and Gram-negative bacteria. The inhibitory activities of both nanocomposites (Ag-FNP and Ag-MNP) were more than those obtained by either Ag-NPs or proteins (FNP, MNP). Minimum inhibitory concentrations (MICs) of Ag-FNP were very low (20 and 10 µg mL-1) against Salmonellatyphimurium and Pseudomonasaerugenosa, respectively, but higher (162 µg mL-1) against E. coli and Listeriamonocytogenes. MICs of Ag-MNP were also very low (20 µg mL-1) against Staphylococcusaureus but higher (325 µg mL-1) against Listeriamonocytogenes. TEM images of Staphylococcusaureus and Salmonellatyphimurium, treated with Ag-FNP and Ag-MNP, at their MIC values, showed asymmetric, wrinkled exterior surfaces, cell deformations, cell depressions, and diminished cell numbers.
| S-EPMC8617916 | biostudies-literature
Project description:Inhibitors and activators of protein-protein interactions are valuable as biological probes and medicinal agents but are often difficult to identify. Herein we describe a high-throughput assay, based upon photonic crystal (PC) biosensors, for the identification of modulators of protein-protein interactions. Through the use of a d-biotin-tris-NTA (BTN) hybrid compound, any His6-tagged protein can be immobilized on the surface of a PC biosensor. Binding of the bound protein to its cognate partner is detected via a shift in the peak wavelength value. We demonstrate this assay with three protein-protein pairs (caspase-9-XIAP, caspase-7-XIAP, FKBP12-FRB) and their small molecule modulators.
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Project description:With the growing antibiotic resistance of Staphylococcus aureus, it is urgent to discover new antimicrobials to solve this problem. By bacterial growth based high-throughput screening, we identified two compounds, C218-0546 and STK848198, with effective antimicrobial activity against S. aureus. This study aims to explore the model of action of the compounds by transcriptomic analysis and other microbiological methods. The transcriptomic data would provide us information about the regulated genes, and hence help us further study the underlying antimicrobial mechanisms by the compounds.
2024-05-20 | PXD052423 |
Project description:BackgroundProtein-protein interactions (PPIs) are intriguing targets for designing novel small-molecule inhibitors. The role of PPIs in various infectious and neurodegenerative disorders makes them potential therapeutic targets . Despite being portrayed as undruggable targets, due to their flat surfaces, disorderedness, and lack of grooves. Recent progresses in computational biology have led researchers to reconsider PPIs in drug discovery.Areas coveredIn this review, we introduce in-silico methods used to identify PPI interfaces and present an in-depth overview of various computational methodologies that are successfully applied to annotate the PPIs. We also discuss several successful case studies that use computational tools to understand PPIs modulation and their key roles in various physiological processes.Expert opinionComputational methods face challenges due to the inherent flexibility of proteins, which makes them expensive, and result in the use of rigid models. This problem becomes more significant in PPIs due to their flexible and flat interfaces. Computational methods like molecular dynamics (MD) simulation and machine learning can integrate the chemical structure data into biochemical and can be used for target identification and modulation. These computational methodologies have been crucial in understanding the structure of PPIs, designing PPI modulators, discovering new drug targets, and predicting treatment outcomes.
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Project description:The caspase recruitment domain (CARD) is present in a large number of proteins. Initially, the CARD was recognized as part of the caspase activation machinery. CARD-CARD interactions play a role in apoptosis and are responsible for the Apaf-1-mediated activation of procaspase-9 in the apoptosome. CARD-containing proteins mediate the inflammasome-dependent activation of proinflammatory caspase-1. More recently, new roles for CARD-containing proteins have been reported in signaling pathways associated with immune responses. The functional role of CARD-containing proteins and CARDs in coordinating apoptosis and inflammatory and immune responses is not completely understood. We have explored the putative cross-talk between apoptosis and inflammation by analyzing the modulatory activity on both the Apaf-1/procaspase-9 interaction and the inflammasome-mediated procaspase-1 activation of CARD-derived polypeptides. To this end, we analyzed the activity of individual recombinant CARDs, rationally designed CARD-derived peptides, and peptides derived from phage display.
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Project description:Discovering small-molecule modulators of protein-protein interactions is a challenging task because of both the generally noncontiguous, large protein surfaces that form these interfaces and the shortage of high-throughput approaches capable of identifying such rare inhibitors. We describe here a robust and flexible methodology that couples disruption of protein-protein complexes to host cell survival. The feasibility of this approach was demonstrated through monitoring a small-molecule-mediated protein-protein association (FKBP12-rapamycin-FRAP) and two cases of dissociation (homodimeric HIV-1 protease and heterodimeric ribonucleotide reductase). For ribonucleotide reductase, we identified cyclic peptide inhibitors from genetically encoded libraries that dissociated the enzyme subunits. A solid-phase synthetic strategy and peptide ELISAs were developed to characterize these inhibitors, resulting in the discovery of cyclic peptides that operate in an unprecedented manner, thus highlighting the strengths of a functional approach. The ability of this method to process large libraries, coupled with the benefits of a genetic selection, allowed us to identify rare, uniquely active small-molecule modulators of protein-protein interactions at a frequency of less than one in 10 million.
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Project description:There is an urgent need for better and safer therapeutic interventions for tuberculosis (TB). We assessed the effects of FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide (HCTZ), metformin, omeprazole, pantoprazole, phenytoin, verapamil, and drug X and Y on the growth of free and intracellular Mycobacterium bovis BCG. Free and intracellular M. bovis BCG were cultured in the presence or absence of the test drugs for 3 to 9 days and then quantified. For both free and intracellular bacteria, cultures that were exposed to furosemide, phenytoin, or drug Y yielded lower bacteria counts compared to drug-free controls (p < 0.05). The same was observed with diazoxide, HCTZ, verapamil, and drug X, but only for intracellular M. bovis BCG (p < 0.05). To assess the effects of the drugs on bactericidal activity of rifampicin, free and intracellular M. bovis BCG were treated with rifampicin alone or in combination with each of the thirteen test drugs for 3 to 9 days. For extracellular bacteria, higher bacteria clearance rates were observed in cultures exposed to rifampicin in combination with amiloride HCl, diazoxide, digoxin, furosemide, HCTZ, metformin, pantoprazole, phenytoin, drug X, or drug Y than those exposed to rifampicin alone, indicating that rifampicin had a synergistic effect with these test drugs. Rifampicin was also synergistic with ambroxol HCl, diazoxide, digoxin, furosemide, HCTZ, omeprazole, pantoprazole, phenytoin, verapamil, and drug X against intracellular M. bovis BCG. The antimycobacterial properties exhibited by the ion transport modulators in this study make them viable candidates as adjuncts to the current anti-TB regimens.
| S-EPMC7700046 | biostudies-literature
Project description:The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, "hot spots", as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ-TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.
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