scholarly journals Consensus sequence design as a general strategy to create hyperstable, biologically active proteins

2018 ◽  
Author(s):  
Matt Sternke ◽  
Katherine W. Tripp ◽  
Doug Barrick
Keyword(s):  
Biological Activity ◽  
High Stability ◽  
Biological Activities ◽  
Consensus Sequence ◽  
Biologically Active ◽  
General Strategy ◽  
Protein Families ◽  
Sequence Design ◽  
Consensus Sequences ◽  
Naturally Occurring

AbstractConsensus sequence design offers a promising strategy for designing proteins of high stability while retaining biological activity since it draws upon an evolutionary history in which residues important for both stability and function are likely to be conserved. Although there have been several reports of successful consensus design of individual targets, it is unclear from these anecdotal studies how often this approach succeeds, and how often it fails. Here, we attempt to assess generality by designing consensus sequences for a set of six protein families with a range of chain-lengths, structures, and activities. We characterize the resulting consensus proteins for stability, structure, and biological activities in an unbiased way. We find that all six consensus proteins adopt cooperatively folded structures in solution. Strikingly, four out of six of these consensus proteins show increased thermodynamic stability over naturally-occurring homologues. Each consensus protein tested for function maintained at least partial biological activity. Though peptide binding affinity by a consensus-designed SH3 is rather low, Km values for consensus enzymes are similar to values from extant homologues. Though consensus enzymes are slower than extant homologues at low temperature, they are faster than some thermophilic enzymes at high temperature. An analysis of sequence properties shows consensus proteins to be enriched in charged residues, and rarified in uncharged polar residues. Sequence differences between consensus and extant homologues are predominantly located at weakly conserved surface residues, highlighting the importance of these residues in the success of the consensus strategy.Significance StatementA major goal of protein design is to create proteins that have high stability and biological activity. Drawing on evolutionary information encoded within extant protein sequences, consensus sequence design has produced several successes in achieving this goal. Here we explore the generality with which consensus design can be used to enhance protein stability and maintain biological activity. By designing and characterizing consensus sequences for six unrelated protein families, we find that consensus design shows high success rates in creating well-folded, hyperstable proteins that retain biological activities. Remarkably, many of these consensus proteins show higher stabilities than naturally-occurring sequences of their respective protein families. Our study highlights the utility of consensus sequence design and informs the mechanisms by which it works.

scholarly journals Consensus sequence design as a general strategy to create hyperstable, biologically active proteins

2019 ◽  
Vol 116 (23) ◽  
pp. 11275-11284 ◽  
Author(s):  
Matt Sternke ◽  
Katherine W. Tripp ◽  
Doug Barrick
Keyword(s):  
Biological Activity ◽  
Biological Activities ◽  
Consensus Sequence ◽  
Biologically Active ◽  
General Strategy ◽  
Sequence Design ◽  
Consensus Sequences ◽  
Stability Structure ◽  
Folded Structures ◽  
And Function

Consensus sequence design offers a promising strategy for designing proteins of high stability while retaining biological activity since it draws upon an evolutionary history in which residues important for both stability and function are likely to be conserved. Although there have been several reports of successful consensus design of individual targets, it is unclear from these anecdotal studies how often this approach succeeds and how often it fails. Here, we attempt to assess generality by designing consensus sequences for a set of six protein families with a range of chain lengths, structures, and activities. We characterize the resulting consensus proteins for stability, structure, and biological activities in an unbiased way. We find that all six consensus proteins adopt cooperatively folded structures in solution. Strikingly, four of six of these consensus proteins show increased thermodynamic stability over naturally occurring homologs. Each consensus protein tested for function maintained at least partial biological activity. Although peptide binding affinity by a consensus-designed SH3 is rather low, Km values for consensus enzymes are similar to values from extant homologs. Although consensus enzymes are slower than extant homologs at low temperature, they are faster than some thermophilic enzymes at high temperature. An analysis of sequence properties shows consensus proteins to be enriched in charged residues, and rarified in uncharged polar residues. Sequence differences between consensus and extant homologs are predominantly located at weakly conserved surface residues, highlighting the importance of these residues in the success of the consensus strategy.

Naphthoquinone Derivatives Isolated from Plants: Recent Advances in Biological Activity

2020 ◽  
Vol 20 (19) ◽  
pp. 2019-2035
Author(s):  
Esmaeil Sheikh Ahmadi ◽  
Amir Tajbakhsh ◽  
Milad Iranshahy ◽  
Javad Asili ◽  
Nadine Kretschmer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Biological Activity ◽  
Small Molecules ◽  
Anticancer Activity ◽  
Clinical Significance ◽  
Phase Ii ◽  
Biological Activities ◽  
Phase Ii Clinical Trials ◽  
Naturally Occurring ◽  
The Subject

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance.

scholarly journals Insight into the Presence of Stilbenes in Medicinal Plants Traditionally Used in Croatian Folk Medicine

2016 ◽  
Vol 11 (6) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Ivana Generalić Mekinić ◽  
Danijela Skroza ◽  
Ivica Ljubenkov ◽  
Višnja Katalinić
Keyword(s):  
Biological Activity ◽  
Medicinal Plants ◽  
Biological Activities ◽  
Folk Medicine ◽  
Free Form ◽  
Naturally Occurring ◽  
Derivatives Of ◽  
Insight Into ◽  
Phenolic Extracts

Over the last years, great interest has arisen concerning plant stilbenes, especially resveratrol, which has a whole spectrum of positive biological activities. In this study, we investigated the presence of resveratrol monomers (trans- and cis- form) and naturally occurring derivatives of fraas-resveratrol (piceid, astringin and isorhapontin) in phenolic extracts of twenty medicinal plants traditionally used in Croatian folk medicine. The investigated compounds were present in the samples, in free form or as glucosides, and the highest share was found in immortelle, common yarrow and Lamiaceae plants. The obtained results indicate that biological activity of selected medicinal plants can be related to the presence of this valuable group of phytochemicals.

scholarly journals Monoterpenes and Their Derivatives—Recent Development in Biological and Medical Applications

2020 ◽  
Vol 21 (19) ◽  
pp. 7078
Author(s):  
Mariola Zielińska-Błajet ◽  
Joanna Feder-Kubis
Keyword(s):  
Biological Activity ◽  
Secondary Metabolites ◽  
Essential Oils ◽  
Structural Modification ◽  
Biological Activities ◽  
Plant Secondary Metabolites ◽  
Biologically Active ◽  
Pivotal Role ◽  
Medical Applications ◽  
Biological And Medical Applications

Monoterpenes, comprising hydrocarbons, are the largest class of plant secondary metabolites and are commonly found in essential oils. Monoterpenes and their derivatives are key ingredients in the design and production of new biologically active compounds. This review focuses on selected aliphatic, monocyclic, and bicyclic monoterpenes like geraniol, thymol, myrtenal, pinene, camphor, borneol, and their modified structures. The compounds in question play a pivotal role in biological and medical applications. The review also discusses anti-inflammatory, antimicrobial, anticonvulsant, analgesic, antiviral, anticancer, antituberculosis, and antioxidant biological activities exhibited by monoterpenes and their derivatives. Particular attention is paid to the link between biological activity and the effect of structural modification of monoterpenes and monoterpenoids, as well as the introduction of various functionalized moieties into the molecules in question.

Syntheses and Biological Activities of triazole-based Sulfonamides

2020 ◽  
Vol 23 (21) ◽  
pp. 2319-2349 ◽  
Author(s):  
Ali Ramazani ◽  
Hamed Sadighian ◽  
Farideh Gouranlou ◽  
Sang W. Joo
Keyword(s):  
Biological Activity ◽  
Biological Activities ◽  
Biological Properties ◽  
Biologically Active ◽  
Potential Biological Activity

: The triazole and sulfonamide compounds are known as biologically active agents that were employed for medicinal applications. These compounds were obtained in different forms by a variety of techniques to vast ranges of applications. The broad biological properties of these compounds have encouraged researchers to design and synthesize triazole-based sulfonamide derivatives as compounds with potential biological activity. In this review, we summarized the synthetic procedures of triazole-based sulfonamide compounds together with their biological activities during the last two decades.

3,4-Dihydroisocoumarins, Interesting Natural Products: Isolation, Organic Syntheses and Biological Activities

2019 ◽  
Vol 16 (1) ◽  
pp. 112-129 ◽  
Author(s):  
Aurelio Ortiz ◽  
Miriam Castro ◽  
Estibaliz Sansinenea
Keyword(s):  
Natural Products ◽  
Biological Activities ◽  
Natural Compounds ◽  
Biologically Active ◽  
Bacterial Strains ◽  
Drug Candidates ◽  
Heterocyclic Molecules ◽  
Naturally Occurring ◽  
Wide Range ◽  
Different Sources

Background:3,4-dihydroisocoumarins are an important small group belonging to the class of naturally occurring lactones isolated from different bacterial strains, molds, lichens, and plants. The structures of these natural compounds show various types of substitution in their basic skeleton and this variability influences deeply their biological activities. These lactones are structural subunits of several natural products and serve as useful intermediates in the synthesis of different heterocyclic molecules, which exhibit a wide range of biological activities, such as anti-inflammatory, antiplasmodial, antifungal, antimicrobial, antiangiogenic and antitumoral activities, among others. Their syntheses have attracted attention of many researchers reporting many synthetic strategies to achieve 3,4-dihydroisocoumarins and other related structures. </P><P> Objective: In this context, the isolation of these natural compounds from different sources, their syntheses and biological activities are reviewed, adding the most recent advances and related developments.Conclusion:This review aims to encourage further work on the isolation and synthesis of this class of natural products. It would be beneficial for synthetic as well as the medicinal chemists to design selective, optimized dihydroisocoumarin derivatives as potential drug candidates, since dihydroisocoumarin scaffolds have significant utility in the development of therapeutically relevant and biologically active compounds.

scholarly journals Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications

2017 ◽  
Vol 242 (15) ◽  
pp. 1482-1489 ◽  
Author(s):  
Edwin D Lephart ◽  
Merritt B Andrus
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Matrix Metalloproteinase ◽  
Human Skin ◽  
Biological Activities ◽  
Gene Array ◽  
Biologically Active ◽  
Nuclear Antigen ◽  
Matrix Metalloproteinase 1 ◽  
Resveratrol Analogs

Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment biological activities on the measured parameters that expand the current knowledge of structure/function relationships. The butyrate and isobutyrate modifications displayed gene expression values significantly above resveratrol and suggest that oral application of these and potentially other resveratrol analogs may yield similar results to improve stability and biological activity to benefit/address various disorders/diseases.

scholarly journals MUSCARI ARMENIACUM LEICHTLIN (GRAPE HYACINTH): PHYTOCHEMISTRY AND BIOLOGICAL ACTIVITIES REVIEW

2019 ◽  
Vol 12 (1) ◽  
pp. 68
Author(s):  
Dmitry Olegovich Bokov
Keyword(s):  
Biological Activity ◽  
Biological Activities ◽  
Biologically Active Substances ◽  
Biologically Active ◽  
Antimutagenic Activity ◽  
Therapeutic Effects ◽  
Herbal Drug ◽  
Ribosome Inactivating Proteins ◽  
Phytochemical Studies ◽  
Active Substances

This review focuses on the Muscari armeniacum Leichtlin (Asparagaceae Juss) biologically active substances composition presented in the Aireal and underground parts and finding their possible therapeutic effects. The systematic review is dedicated to the composition of biologically active substances, including recent advances in the biological activity investigation, phytochemical studies, and biotechnology methods of plant material producing. Various electronic search engines such as Google, Google Scholar, scientific literature, publishing sites, and electronic databases such as PubMed, Wiley, Springer, and Science Direct had been searched and data obtained. Other online academic libraries such as E-library and specific ethnopharmacological literature had been searched systematically for more exhaustive information on the crude herbal drug. The chemical composition of M. armeniacum biologically active substances is established; it contains anthocyanins (delphinidin and cyanidin derivatives), homoisoflavonoids, polyhydroxylated pyrrolizidine alkaloids (hyacinthacines A1, A2, A3, and B3), oligoglycosides (Muscarosides), and ribosome-inactivating proteins (musarmins). Recent physicochemical analytical procedures for components determination and hyacinthacines synthesis pathways are mentioned. Moreover, future prospects and trends in the research of this plant have been proposed. We have reviewed researches conducted on M. armeniacum especially in areas of its use in medicine, phytochemicals, biological activity, and developed analytical methods. M. armeniacum possesses antioxidant, antimutagenic activity, and specific glycosidase inhibitory activity; M. armeniacum can be used for the production of potential anticancer, antiviral, antidiabetic, and anti-obesity drugs. It should be noted that more pharmacognostic, pharmacological studies are needed for giving further information on the clinical practice and standardization procedures for the crude herbal drug.

scholarly journals Yeast Particle Encapsulation of Scaffolded Terpene Compounds for Controlled Terpene Release

Foods ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1207
Author(s):  
Ernesto R. Soto ◽  
Florentina Rus ◽  
Hanchen Li ◽  
Carli Garceau ◽  
Jeffrey Chicca ◽  
...  
Keyword(s):  
Biological Activity ◽  
Cell Walls ◽  
Room Temperature ◽  
Biological Activities ◽  
Membrane Permeation ◽  
Stimuli Responsive ◽  
Naturally Occurring ◽  
Volatile Solids ◽  
Pharmaceutical Industries ◽  
Particle Encapsulation

Terpenes are naturally occurring compounds produced by plants that are of great commercial interest in the food, agricultural, cosmetic, and pharmaceutical industries due to their broad spectra of antibacterial, antifungal, anthelmintic, membrane permeation enhancement, and antioxidant biological activities. Applications of terpenes are often limited by their volatility and the need for surfactants or alcohols to produce stable, soluble (non-precipitated) products. Yeast particles (YPs) are hollow, porous microspheres that have been used for the encapsulation of terpenes (YP terpenes) by passive diffusion of terpenes through the porous YP cell walls. We here report the development of a second generation YP encapsulated terpene technology that incorporates the stimuli-responsive control of terpene release using biodegradable pro-terpene compounds (YP pro-terpenes). YP terpenes and YP pro-terpenes were both produced, in which high levels of carvacrol, eugenol, thymol and geraniol were encapsulated. The YP pro-terpenes show higher encapsulation stability than YP terpenes due to pro-terpenes being non-volatile solids at room temperature and stable in suspensions at neutral pH. YP pro-terpenes and YP terpenes were evaluated for biological activity in antibacterial, antifungal and anthelmintic assays. The YP pro-terpenes retained the full biological activity of the parent terpene compound.

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