scholarly journals Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 376 ◽  
Author(s):  
Danielle Demers ◽  
Matthew Knestrick ◽  
Renee Fleeman ◽  
Rahmy Tawfik ◽  
Ala Azhari ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Small Molecules ◽  
Endophytic Fungi ◽  
Dna Methyltransferase ◽  
Leishmania Donovani ◽  
Screening Program ◽  
Single Target ◽  
New Antibiotics

There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment.

scholarly journals Editorial on Special Issue “Tuberculosis Drug Discovery and Development 2019”

2020 ◽  
Vol 10 (17) ◽  
pp. 6069
Author(s):  
Claudia Sala ◽  
Laurent Roberto Chiarelli ◽  
Giovanna Riccardi
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Human Health ◽  
Cause Of Death ◽  
Etiological Agent ◽  
Special Issue ◽  
Drug Discovery And Development ◽  
Global Challenge

Mycobacterium tuberculosis, the etiological agent of human tuberculosis (TB), represents a global challenge to human health since it is the main cause of death by an infectious disease worldwide [...]

Aim for the Readers! Bromodomains As New Targets Against Chagas’ Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6544-6563
Author(s):  
Victoria Lucia Alonso ◽  
Luis Emilio Tavernelli ◽  
Alejandro Pezza ◽  
Pamela Cribb ◽  
Carla Ritagliati ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Chagas Disease ◽  
Causative Agent ◽  
Current Knowledge ◽  
Sequence Similarity ◽  
Lysine Acetylation ◽  
Specific Manner ◽  
Lysine Residues ◽  
Antiparasitic Drugs

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

scholarly journals Infection rates with Leishmania donovani and Mycobacterium tuberculosis in a village in eastern Sudan

2004 ◽  
Vol 9 (12) ◽  
pp. 1305-1311 ◽  
Author(s):  
Sayda Hassan el-Safi ◽  
Nuha Hamid ◽  
Ahmed Omer ◽  
Ahmed Abdel-Haleem ◽  
Awad Hammad ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Leishmania Donovani ◽  
Infection Rates ◽  
Eastern Sudan

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

scholarly journals Fine-tuning of a generative neural network for designing multi-target compounds

2021 ◽  
Author(s):  
Thomas Blaschke ◽  
Jürgen Bajorath
Keyword(s):  
Neural Network ◽  
Small Molecules ◽  
De Novo ◽  
Pharmaceutical Research ◽  
Generative Models ◽  
Fine Tuning ◽  
Data Sets ◽  
Single Target ◽  
Fine Tune ◽  
Target Activity

AbstractExploring the origin of multi-target activity of small molecules and designing new multi-target compounds are highly topical issues in pharmaceutical research. We have investigated the ability of a generative neural network to create multi-target compounds. Data sets of experimentally confirmed multi-target, single-target, and consistently inactive compounds were extracted from public screening data considering positive and negative assay results. These data sets were used to fine-tune the REINVENT generative model via transfer learning to systematically recognize multi-target compounds, distinguish them from single-target or inactive compounds, and construct new multi-target compounds. During fine-tuning, the model showed a clear tendency to increasingly generate multi-target compounds and structural analogs. Our findings indicate that generative models can be adopted for de novo multi-target compound design.

scholarly journals Antimalarial Activity of the Myxobacterial Macrolide Chlorotonil A

2014 ◽  
Vol 58 (11) ◽  
pp. 6378-6384 ◽  
Author(s):  
Jana Held ◽  
Tamirat Gebru ◽  
Markus Kalesse ◽  
Rolf Jansen ◽  
Klaus Gerth ◽  
...  
Keyword(s):  
Screening Program ◽  
Antimalarial Activity ◽  
Stage Iv ◽  
Short Exposure ◽  
Parasite Development ◽  
Content Type ◽  
Highly Active ◽  
New Antibiotics ◽  
Further Development ◽  
Antimalarial Action

ABSTRACTMyxobacteria are Gram-negative soil-dwelling bacteria belonging to the phylumProteobacteria. They are a rich source of promising compounds for clinical application, such as epothilones for cancer therapy and several new antibiotics. In the course of a bioactivity screening program of secondary metabolites produced bySorangium cellulosumstrains, the macrolide chlorotonil A was found to exhibit promising antimalarial activity. Subsequently, we evaluated chlorotonil A againstPlasmodium falciparumlaboratory strains and clinical isolates from Gabon. Chlorotonil A was highly active, with a 50% inhibitory concentration between 4 and 32 nM; additionally, no correlations between the activities of chlorotonil A and artesunate (rho, 0.208) or chloroquine (rho, −0.046) were observed.Per ostreatment ofPlasmodium berghei-infected mice with four doses of as little as 36 mg of chlorotonil A per kg of body weight led to the suppression of parasitemia with no obvious signs of toxicity. Chlorotonil A acts against all stages of intraerythrocytic parasite development, including ring-stage parasites and stage IV to V gametocytes, and it requires only a very short exposure to the parasite to exert its antimalarial action. Conclusively, chlorotonil A has an exceptional and unprecedented profile of action and represents an urgently required novel antimalarial chemical scaffold. Therefore, we propose it as a lead structure for further development as an antimalarial chemotherapeutic.

scholarly journals SAR by kinetics for drug discovery in protein misfolding diseases

2018 ◽  
Vol 115 (41) ◽  
pp. 10245-10250 ◽  
Author(s):  
Sean Chia ◽  
Johnny Habchi ◽  
Thomas C. T. Michaels ◽  
Samuel I. A. Cohen ◽  
Sara Linse ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Misfolding ◽  
Amyloid Beta Peptide ◽  
Oligomer Formation ◽  
Chemical Derivatives ◽  
Structure Activity ◽  
Beta Peptide ◽  
Misfolding Diseases ◽  
Aβ Oligomer

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

2020 ◽  
Author(s):  
Chao Wang ◽  
Juan Diez ◽  
Hajeung Park ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Hydroxamic Acid ◽  
Therapeutic Potential ◽  
Preceding Paper ◽  
Close Relative ◽  
Specific Inhibition ◽  
Selective Inhibitors

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

scholarly journals The thick waxy coat of mycobacteria, a protective layer against antibiotics and the host's immune system

2020 ◽  
Vol 477 (10) ◽  
pp. 1983-2006 ◽  
Author(s):  
Sarah M. Batt ◽  
David E. Minnikin ◽  
Gurdyal S. Besra
Keyword(s):  
Infectious Disease ◽  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Mortality Rate ◽  
Cell Envelope ◽  
Protective Layer ◽  
Structure And Function ◽  
Complex Lipids ◽  
And Function

Tuberculosis, caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb), is the leading cause of death from an infectious disease, with a mortality rate of over a million people per year. This pathogen's remarkable resilience and infectivity is largely due to its unique waxy cell envelope, 40% of which comprises complex lipids. Therefore, an understanding of the structure and function of the cell wall lipids is of huge indirect clinical significance. This review provides a synopsis of the cell envelope and the major lipids contained within, including structure, biosynthesis and roles in pathogenesis.

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