Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future.
Ontology highlight
ABSTRACT:
SUBMITTER: Stofberg ML
PROVIDER: S-EPMC8616389 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.
| S-EPMC4235713 | biostudies-literature
Project description:The evolution of biocrystallography from the pioneers' time to the present era of global biology is presented in relation to the development of methodological and instrumental advances for molecular sample preparation and structure elucidation over the last 6 decades. The interdisciplinarity of the field that generated cross-fertilization between physics- and biology-focused themes is emphasized. In particular, strategies to circumvent the main bottlenecks of biocrystallography are discussed. They concern (i) the way macromolecular targets are selected, designed, and characterized, (ii) crystallogenesis and how to deal with physical and biological parameters that impact crystallization for growing and optimizing crystals, and (iii) the methods for crystal analysis and 3D structure determination. Milestones that have marked the history of biocrystallography illustrate the discussion. Finally, the future of the field is envisaged. Wide gaps of the structural space need to be filed and membrane proteins as well as intrinsically unstructured proteins still constitute challenging targets. Solving supramolecular assemblies of increasing complexity, developing a "4D biology" for decrypting the kinematic changes in macromolecular structures in action, integrating these structural data in the whole cell organization, and deciphering biomedical implications will represent the new frontiers.
| S-EPMC2929629 | biostudies-literature
Project description:The specialty of nutrition in critical care is relatively modern, and accordingly, trial design has progressed over recent decades. In the past, small observational and physiological studies evolved to become small single-centre comparative trials, but these had significant limitations by today's standards. Power calculations were often not undertaken, outcomes were not specified a priori, and blinding and randomisation were not always rigorous. These trials have been superseded by larger, more carefully designed and conducted multi-centre trials. Progress in trial conduct has been facilitated by a greater understanding of statistical concepts and methodological design. In addition, larger numbers of potential study participants and increased access to funding support trials able to detect smaller differences in outcomes. This narrative review outlines why critical care nutrition research is unique and includes a historical critique of trial design to provide readers with an understanding of how and why things have changed. This review focuses on study methodology, population group, intervention, and outcomes, with a discussion as to how these factors have evolved, and concludes with an insight into what we believe trial design may look like in the future. This will provide perspective on the translation of the critical care nutrition literature into clinical practice.
| S-EPMC7760682 | biostudies-literature
Project description:The uses of antiviral agents are increasing in the new era along with the development of vaccines for the effective control of viral diseases. The main aims of antiviral agents are to minimize harm to the host system and eradicate deadly viral diseases. However, the replications of viruses in host system represent a massive therapeutic challenge than bacteria and fungi. Antiviral drugs not just penetrate to disrupt the virus’ cellular divisions but also have a negative impact on normal physiological pathways in the host. Due to these issues, antiviral agents have a narrow therapeutic index than antibacterial drugs. Nephrotoxicity is the main adverse reaction of antiviral drugs in human and animals. In this chapter, we summarize the antiviral agents’ past, present and future perspectives with the main focus on the brief history of antiviral in animals, miscellaneous drugs, natural products, herbal and repurposing drugs.
| S-EPMC7120554 | biostudies-literature
Project description:The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of loricrin, which is a major CE component. Despite its quantitative significance, loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives.
| S-EPMC7177664 | biostudies-literature
Project description:In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ?-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ?-lactamases, in some cases act as "slow substrates" or inhibitors of ?-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting ?-lactamases serves as a major rationale for expansion of this class of ?-lactams. We describe the initial discovery and development of the carbapenem family of ?-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.
| S-EPMC3195018 | biostudies-literature
Project description: Not available
| S-EPMC2194748 | biostudies-literature
Project description:Integrons are versatile gene acquisition systems commonly found in bacterial genomes. They are ancient elements that are a hot spot for genomic complexity, generating phenotypic diversity and shaping adaptive responses. In recent times, they have had a major role in the acquisition, expression, and dissemination of antibiotic resistance genes. Assessing the ongoing threats posed by integrons requires an understanding of their origins and evolutionary history. This review examines the functions and activities of integrons before the antibiotic era. It shows how antibiotic use selected particular integrons from among the environmental pool of these elements, such that integrons carrying resistance genes are now present in the majority of Gram-negative pathogens. Finally, it examines the potential consequences of widespread pollution with the novel integrons that have been assembled via the agency of human antibiotic use and speculates on the potential uses of integrons as platforms for biotechnology.
| S-EPMC4054258 | biostudies-literature
Project description:In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care.
| S-EPMC10495438 | biostudies-literature
Project description:mRNA vaccines have emerged as promising alternative platforms to conventional vaccines. Their ease of production, low cost, safety profile and high potency render them ideal candidates for prevention and treatment of infectious diseases, especially in the midst of pandemics. The challenges that face in vitro transcribed RNA were partially amended by addition of tethered adjuvants or co-delivery of naked mRNA with an adjuvant-tethered RNA. However, it wasn't until recently that the progress made in nanotechnology helped enhance mRNA stability and delivery by entrapment in novel delivery systems of which, lipid nanoparticles. The continuous advancement in the fields of nanotechnology and tissue engineering provided novel carriers for mRNA vaccines such as polymeric nanoparticles and scaffolds. Various studies have shown the advantages of adopting mRNA vaccines for viral diseases and cancer in animal and human studies. Self-amplifying mRNA is considered today the next generation of mRNA vaccines and current studies reveal promising outcomes. This review provides a comprehensive overview of mRNA vaccines used in past and present studies, and discusses future directions and challenges in advancing this vaccine platform to widespread clinical use.
| S-EPMC9459002 | biostudies-literature