scholarly journals Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2868 ◽  
Author(s):  
Anatol Spork ◽  
Stefan Koppermann ◽  
Stephanie Schier (née Wohnig) ◽  
Ruth Linder ◽  
Christian Ducho
Keyword(s):  
Antitumor Agents ◽  
Widespread Application ◽  
Core Motif ◽  
Nucleoside Antibiotics ◽  
Drug Candidates ◽  
Peptidoglycan Biosynthesis ◽  
Sar Studies ◽  
Naturally Occurring ◽  
Promising Target ◽  
Order Of Magnitude

Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived ‘nucleoside antibiotics’ target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products. As part of detailed structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5′,6′-anti-configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates.

scholarly journals Aminoribosylated Analogues of Muraymycin Nucleoside Antibiotics

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3085 ◽  
Author(s):  
Daniel Wiegmann ◽  
Stefan Koppermann ◽  
Christian Ducho
Keyword(s):  
Structural Motif ◽  
The Novel ◽  
Reference Compound ◽  
Inhibitory Potency ◽  
Nucleoside Antibiotics ◽  
Peptidoglycan Biosynthesis ◽  
Sar Studies ◽  
Naturally Occurring ◽  
Key Enzyme

Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one subclass of such naturally occurring MraY inhibitors. As part of structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report on novel derivatives with different attachment of one characteristic structural motif, i.e., the aminoribose moiety normally linked to the muraymycin glycyluridine core unit. Based on considerations derived from an X-ray co-crystal structure, we designed and synthesised muraymycin analogues having the aminoribose attached (via a linker) to either the glycyluridine amino group or to the uracil nucleobase. Reference compounds bearing the non-aminoribosylated linker units were also prepared. It was found that the novel aminoribosylated analogues were inactive as MraY inhibitors in vitro, but that the glycyluridine-modified reference compound retained most of the inhibitory potency relative to the unmodified parent muraymycin analogue. These results point to 6′-N-alkylated muraymycin analogues as a potential novel variation of the muraymycin scaffold for future SAR optimisation.

scholarly journals Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

2016 ◽  
Vol 12 ◽  
pp. 769-795 ◽  
Author(s):  
Daniel Wiegmann ◽  
Stefan Koppermann ◽  
Marius Wirth ◽  
Giuliana Niro ◽  
Kristin Leyerer ◽  
...  
Keyword(s):  
Natural Products ◽  
Antibacterial Agents ◽  
Peptide Antibiotics ◽  
Peptidoglycan Biosynthesis ◽  
Sar Studies ◽  
Current State ◽  
Naturally Occurring ◽  
Structure Activity ◽  
Key Enzyme ◽  
State Of Research

Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.

Progress in analgesic development: How to assess its real merits?

2021 ◽  
Vol 16 ◽  
Author(s):  
Igor Kissin
Keyword(s):  
Drug Evaluation ◽  
Previous Treatment ◽  
Widespread Application ◽  
Drug Candidates ◽  
Advantages And Disadvantages ◽  
Inflammatory Drugs ◽  
Pain Analgesics ◽  
Approved Drugs ◽  
Multifactorial Approach ◽  
Opioid Receptor Agonists

Background: Assessing analgesic drugs developed over preceding 50 years demonstrated that very intensive efforts directed at diverse molecular pain targets produced thousands of PubMed articles and the introduction of more than 50 new analgesics. Nevertheless, these analgesics did not have a sufficiently broad spectrum of action and level of effectiveness to demonstrably affect the use of opioids or nonsteroidal anti-inflammatory drugs for the treatment of pain. Analgesics in current are only modestly effective in chronic pain (at least with respect to neuropathic pain), and the widespread application of mu opioid receptor agonists for this purpose culminated in the global "opioid crisis”. The introduction of every new drug is regarded as an important success, at least initially. Assessing the merit of a new analgesic is extremely complicated. Objective: The aim of this article is to describe an approach that combines very different categories of drug evaluation – multifactorial approach to assessment of new analgesics. It is based on conclusiveness of clinical trials, novelty of a drug’s molecular target, a drug’s commercial appeal, and the interest in a drug reflected by scientometric indices. Results: This approach was applied to analgesics developed in 1982-2016. It shows that although several new agents have completely novel mechanisms of action, all newly approved drugs, and drug candidates, demonstrated the same persistent problems: relatively low therapeutic advantage over previous treatment and narrow spectrum of use in different types of pain, compared to opioids or NSAIDs. Conclusion: The use of the suggested multifactorial approach to drug assessment may provide a better view of the whole spectrum of analgesics advantages and disadvantages.

QSAR Studies to Predict Activity of HSP90 Inhibitors

2021 ◽  
Vol 21 ◽  
Author(s):  
Vaishali M. Patil ◽  
Neeraj Masand ◽  
Satya P. Gupta ◽  
Brian S. J. Blagg
Keyword(s):  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
New Drugs ◽  
Signaling Proteins ◽  
Hsp90 Inhibitors ◽  
Oncogenic Signaling ◽  
Qsar Studies ◽  
Sar Studies ◽  
Promising Target ◽  
Qsar Models

: Heat shock protein 90 (HSP90) is a multichaperone complex that mediates the maturation and stability of a variety of oncogenic signaling proteins. HSP90 has emerged as a promising target for the development of anticancer agents. Heterocyclic chemical moieties with HSP90 inhibitory activity were studied continuously during the last decades, and resulting data were applied by medicinal chemists to design and develop new drugs. Their structure-activity relationship (SAR) studies and QSAR models have been derived to assist the current drug development process. The QSAR models are obtained via multiple linear regression (MLR) and non-linear approaches. Interpretation of the reported model highlights the core template required to design novel, potent HSP90 inhibitors to be used as anticancer agents.

scholarly journals Caspofungin and LTX-315 inhibit SARS-CoV-2 replication by targeting the nsp12 polymerase

2020 ◽  
Author(s):  
Min Wang ◽  
Fei Ye ◽  
Jiaqi Su ◽  
Jingru Zhao ◽  
Bin Yuan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Vero Cells ◽  
Polymerase Activity ◽  
Structural Protein ◽  
Live Virus ◽  
Drug Candidates ◽  
Virtual Screen ◽  
Virus Assay ◽  
Promising Target

Abstract The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously designated as 2019-nCoV) outbreak has caused global concern1. Currently, there are no clinically approved specific drugs or vaccines available for this virus. The viral polymerase is a promising target for developing broad- spectrum antiviral drugs. Here, based on the highly similar structure of SARS- CoV non-structural protein 12 (nsp12) polymerase subunit2, we applied virtual screen for the available compounds, including both the FDA-approved and under- clinic drugs, to identify potential antiviral molecules against SARS-CoV-2. We found two drugs, the clinically approved anti-fungi drug Caspofungin Acetate (Cancidas) and the oncolytic peptide LTX-315, can bind SARS-CoV-2 nsp12 protein to block the polymerase activity in vitro. Further live virus assay revealed that both Caspofungin Acetate and LTX-315 can effectively inhibit SARS-CoV-2 replication in vero cells. These findings present promising drug candidates for treatment of related diseases and would also stimulate the development of pan- coronavirus antiviral agents.Authors Min Wang, Fei Ye, Jiaqi Su, Jingru Zhao, and Bin Yuan contributed equally to this work.

scholarly journals Cover Feature: Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics (ChemMedChem 8/2018)

ChemMedChem ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. 763-763
Author(s):  
Stefan Koppermann ◽  
Zheng Cui ◽  
Patrick D. Fischer ◽  
Xiachang Wang ◽  
Jannine Ludwig ◽  
...  
Keyword(s):  
Nucleoside Antibiotics ◽  
Target Interaction ◽  
Naturally Occurring

Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents

2021 ◽  
Vol 21 ◽  
Author(s):  
Paulo Fernando da Silva Santos-Júnior ◽  
Martine Schmitt ◽  
João Xavier de Araújo-Júnior ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Combined Therapy ◽  
Experimental Studies ◽  
New Drugs ◽  
Host Cells ◽  
Sar Studies ◽  
Promising Target ◽  
Ic50 Value ◽  
Leishmania Spp ◽  
Etiological Agents ◽  
Antiparasitic Agents

: Trypanosomatidae family belongs to the Kinetoplastida order, which consists of obligatory parasites that affect plants and all classes of vertebrates, especially humans and insects. Among the heteroxenic parasites, Leishmania spp., Trypanosoma cruzi, and T. brucei are protozoa of most significant interest for medicinal chemistry, being etiological agents of Leishmaniasis, Chagas, and Sleep Sickness diseases, respectively. Currently, inefficient pharmacotherapy, especially in chronic phases and low selectivity towards parasite/host cells, justifies the need to discover new drugs to treat them effectively. Among other targets, the sterol 14α-demethylase (CYP51), an enzyme responsible for ergosterol's biosynthesis in Trypanosomatidae parasites, has received more attention in the development of new bioactive compounds. In this context, antifungal ravuconazole proved to be the most promising drug among this class against T. cruzi, being used in combined therapy with Bnz in clinic trials. Non-antifungal inhibitors, such as VFV and VNF, have shown promising results against T. cruzi and T.brucei, respectively, being tested in Bnz-combined therapies. Among the experimental studies involving azoles, compound (15) was found to be the most promising derivative, displaying an IC50 value of 0.002 µM against amastigotes from T. cruzi, in addition to being non-toxic and highly selective towards TcCYP51 (< 25 nM). Interestingly, imidazole analog (16) was active against infectious forms of these three parasites, demonstrating Ki values of 0.17, 0.02, and 0.36 nM for CYP51 from T. cruzi, T. brucei, and L. infantum. Finally, this review will address promising inhibitors targeting sterol 14α-demethylase (CYP51) from Trypanosomatidae parasites, highlighting SAR studies, interactions with this target, and recent contributions and advances in the field, as well.

scholarly journals Homology Modeling and Virtual Screening Studies of Antigen MLAA-42 Protein: Identification of Novel Drug Candidates against Leukemia—An In Silico Approach

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Ihsan A. Shehadi ◽  
Huda R. M. Rashdan ◽  
Aboubakr H. Abdelmonsef
Keyword(s):  
Virtual Screening ◽  
Homology Modeling ◽  
Protein Identification ◽  
Binding Affinities ◽  
Monocytic Leukemia ◽  
Drug Candidates ◽  
Promising Target ◽  
Leukemia Treatment ◽  
Potent Drug ◽  
Novel Drug

Monocytic leukemia-associated antigen-42 (MLAA-42) is associated with excessive cell division and progression of leukemia. Thus, human MLAA-42 is considered as a promising target for designing of new lead molecules for leukemia treatment. Herein, the 3D model of the target was generated by homology modeling technique. The model was then evaluated using various cheminformatics servers. Moreover, the virtual screening studies were performed to explore the possible binding patterns of ligand molecules to MLAA’s active site pocket. Thirteen ligand molecules from the ChemBank™ database were identified as they showed good binding affinities, scaffold diversity, and preferential ADME properties which may act as potent drug candidates against leukemia. The study provides the way to identify novel therapeutics with optimal efficacy, targeting MLAA-42.

scholarly journals Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau

2019 ◽  
Vol 20 (17) ◽  
pp. 4283 ◽  
Author(s):  
Hyeanjeong Jeong ◽  
Seulgi Shin ◽  
Jun-Seok Lee ◽  
Soo Hyun Lee ◽  
Ja-Hyun Baik ◽  
...  
Keyword(s):  
Side Effects ◽  
Mouse Models ◽  
Cognitive Abilities ◽  
Therapeutic Strategy ◽  
Hdac Inhibitors ◽  
Tau Pathology ◽  
Drug Candidates ◽  
Promising Target ◽  
Epigenetic Remodeling ◽  
Tau Aggregation

Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer’s disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse models. Although emerged as a promising target for AD, most of the HDAC inhibitors are poorly selective and could cause unwanted side effects. Here we show that tau is one of the cytosolic substrates of HDAC and the treatment of HDAC inhibitors such as Scriptaid, M344, BML281, and SAHA could increase the level of acetylated tau, resulting in the activation of tau pathology.

scholarly journals Mass-correlated rotational Raman spectra with high resolution, broad bandwidth, and absolute frequency accuracy

2018 ◽  
Vol 115 (20) ◽  
pp. 5072-5076 ◽  
Author(s):  
Christian Schröter ◽  
Jong Chan Lee ◽  
Thomas Schultz
Keyword(s):  
Raman Spectra ◽  
Optical Excitation ◽  
Rotational Transition ◽  
Observation Time ◽  
Absolute Frequency ◽  
Naturally Occurring ◽  
Order Of Magnitude ◽  
Quantum Wave ◽  
External Clock ◽  
Time And Energy

We present mass-correlated rotational alignment spectroscopy, based on the optical excitation of a coherent rotational quantum wave and the observation of temporal wave interferences in a mass spectrometer. Combined electronic and opto-mechanical delays increased the observation time and energy resolution by an order of magnitude compared with preceding time-domain measurements. Rotational transition frequencies were referenced to an external clock for accurate absolute frequency measurements. Rotational Raman spectra for six naturally occurring carbon disulfide isotopologues were resolved with 3 MHz resolution over a spectral range of 500 GHz. Rotational constants were determined with single-kilohertz accuracy, competitive with state-of-the-art frequency domain measurements.

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