A Theme Issue to Celebrate Professor Robert Verpoorte's 75th Birthday: "The Past, Current, and Future of Natural Products".

Dear Colleagues, [...].

A novel challenge of nondestructive analysis on OGATA Koan's sealed medicine by muonic X-ray analysis.

OGATA Koan (1810-63) was a physician and the director of Tekijuku, and he contributed to Western medicine in the late Edo period. Osaka University preserves two of his medicine chests. One of the chests, which was used in his last years (the second chest) contained 22 glass bottles and 6 wooden cylinders. These bottles and cylinders contained formulated medicines; however, about half cannot be opened because of the long-term storage. It is necessary to comprehend the physical property of both the containers and their contents for investigation of this adequate preservation method; however, destructive analysis is not allowed. To analyze the medicines sealed in the glass bottles, we focused on muonic X-ray analysis, which has high transmittance. First, we certified the analytical methods using a historical medicinal specimen preserved in Osaka University. Thereafter, we applied the method on the bottles stored in the second chest. X-ray fluorescence identified the glass of those bottles to be lead potash glass. Among these bottles, we chose the bottle with the label "," which contains white powdered medication, for muonic X-ray analysis. We identified the contents of the medication in the glass to be Hg2Cl2. Through this study, we first applied muonic X-ray analysis on the medical inheritances and succeeded to detect the elements contained both in the container and in the contents of the sealed bottle. This would be a new method for nondestructive analysis of such cultural properties.

30 Years of Biotherapeutics Development-What Have We Learned?

Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.

What is hidden in the biodiversity? The role of natural products and medicinal chemistry in the drug discovery process.

This manuscript describes the role of natural products in the process of drug discovery. In fact, several different natural compounds have been used as inspiration to develop new drugs. Some relevant examples are presented in chronological order.

The role of natural products in modern drug discovery.

The global medicine market is about 1.1 trillion US dollars. About 35 percent of medicines have originated from natural products. Brazil presents the largest biodiversity in the world, with more than 50,000 species of higher plants. However, few innovative products have been developed in Brazil from active constituents derived from the Brazilian biodiversity. Scientific evidences on plants and venoms have been internationally published by Brazilian scientists over the last 4 decades; but few examples of innovative products are commercially available. Few examples include the anti-hypertensive drug captopril first identified in the venom of the Brazilian viper Bothrops jararaca by Professor Sergio Ferreira; and some phytotherapeutic agents such as Acheflan®, Syntocalmy® and Melagrião® produced by standardized plant extracts with scientific proof of safety, efficacy and quality. Still, only Acheflan® and Melagrião® are obtained from native Brazilian plants. Several issues contribute to the lack of innovative products from the Brazilian biodiversity, but in my opinion, the most challenging ones are i) the lack of specific regulations to allow researchers and companies to access biodiversity for the purposes of scientific and technological innovation; and ii) the absence of a long-term government program to support research and innovation in this field.

A fascinating story of the discovery & development of biologicals for use in clinical medicine.

A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be prescribing for a patient evaluated in the morning outpatient department. For him/her, this is now routine, and the question of 'Who', 'How' and 'When' about these biologicals would be the last thing on their mind. However, for those who came to the medical profession in the 1950s, 1960s and 1970s, these targeted drugs are nothing short of 'miracles'. It would be a fascinating story for the young doctor to learn about the long journey that the dedicated biomedical scientists of yesteryears took to reach the final destination of producing such wonder drugs. The story is much like an interesting novel, full of twists and turns, heart-breaking failures and glorious successes. The biologicals acting as 'targeted therapy' have not only changed the natural history of a large number of incurable/uncontrollable diseases but have also transformed the whole approach towards drug development. From the classical empirical process, there is now a complete shift towards understanding the disease pathobiology focusing on the dysregulated molecule(s), targeting them with greater precision and aiming for better results. Seminal advances in understanding the disease mechanism, development of remarkably effective new technologies, greater knowledge of the human genome and genetic medicine have all made it possible to reach the stage where artificially developed 'targeted' drugs are now therapeutically used in routine clinical medicine.

Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick.

Covering: 1893 to 2017Harold Raistrick was involved in the discovery of many of the most important classes of fungal metabolites during the 20th century. This review focusses on how these discoveries led to developments in isotopic labelling, biomimetic chemistry and the discovery, analysis and exploitation of biosynthetic gene clusters for major classes of fungal metabolites including: alternariol; geodin and metabolites of the emodin pathway; maleidrides; citrinin and the azaphilones; dehydrocurvularin; mycophenolic acid; and the tropolones. Key recent advances in the molecular understanding of these important pathways, including the discovery of biosynthetic gene clusters, the investigation of the molecular and chemical aspects of key biosynthetic steps, and the reengineering of key components of the pathways are reviewed and compared. Finally, discussion of key relationships between metabolites and pathways and the most important recent advances and opportunities for future research directions are given.

A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review.

Importance: Accelerated approval (AA) is a US Food and Drug Administration (FDA) expedited program intended to speed the approval of drugs and biologics that may demonstrate a meaningful advantage over available therapies for diseases that are serious or life-threatening. Observations: This review describes all malignant hematology and oncology AAs from inception of the program on December 11, 1992, to May 31, 2017. During this period, the FDA granted AA to 64 malignant hematology and oncology products for 93 new indications. Of these AAs, 53 were for new molecular entities. Overall, the end point of response rate, including hematologic response rates, accounted for most AAs (81 [87%]), followed by time-to-event end points of progression-free survival or time to progression (8 [9%]) and disease-free survival or recurrence-free survival (4 [4%]). Single-arm trial designs provided the data for 67 (72%) of the initial AA indications. Of the 93 AAs, 51 (55%) have fulfilled their postmarketing requirement and verified benefit in a median of 3.4 years after their initial AA. Thirty-seven (40%) indications have not yet completed confirmatory trial(s) or verified benefit, and 5 indications receiving AA (5%) have been withdrawn from the market. Conclusions and Relevance: The use of the AA program during the past 25 years has increased over time, and only a small portion of indications under the AA program fail to verify clinical benefit. For patients with serious or life-threatening oncologic diseases, AA brings products to the market years before confirmatory trials are typically completed.

Advanced natural products chemistry research in China between 2015 and 2017.

In this review, we intensively focus on the advances in research of natural products (NPs) discovery carried out by domestic scholars in China from 2015 through 2017. In general, a total of 1811 publications (1479 in English and 332 in Chinese) were accumulated regarding newly isolated NPs from plants, microorganisms, and marine sources. As a result, 277 selected papers concerning naturally occurring compounds with extraordinary frameworks, origins, and promising activities were discussed in this review article, mainly organized according to their structural classes and novelties.

Hymenoptera venoms used to produce allergen extracts.

OBJECTIVE: To review the methods and materials used for collection, purification, commercial production, and clinical application of Hymenoptera venoms. DATA SOURCES: Most of the sources for this review are the experience and expertise of the authors. Published reports and review articles on Hymenoptera venom collection and production were identified through database searches (PubMed). STUDY SELECTIONS: Studies describing the methods for Hymenoptera venom collection and production were selected for review. RESULTS: Meticulous methods for identification and collection of the insects are required. Collection and purification of the venoms from the insects are based on validated methods and result in a commercial extract that is standardized for the major allergenic proteins required for accurate diagnosis and safe and effective treatment of patients allergic to insect sting. The steps required for mixing, purifying, testing, and standardizing the products are described. CONCLUSION: Hymenoptera venom extracts were developed using many new methods for the collection, purification, and commercial production of the unique materials required for this product. Clinical applications for diagnosis and treatment are affected by the integrity and stability of the allergens after processing and purification.

From Pharmacognosia to DNA-Based Medicinal Plant Authentication - Pharmacognosy through the Centuries.

For centuries, pharmacognosy was essential for the identification, quality, purity, and, until the end of the 18th century, even for the efficacy of medicinal plants. Since the 19th century, it concentrated on authenticity, purity, quality and the analysis of active substances, and was established as an academic branch discipline within pharmacy and continuously developed into a modern, highly sophisticated science. Even though the paradigm in pharmacy changed in the 19th century with the discovery of morphine and concentrated on single substances that could be synthesized fast by the upcoming industry, medicinal plants always remained an important element of the Materia medica, and during the last decades, medicinal plants continue to be a source of remedies, and natural products are an inspiration for new medicine. In this research, pharmacognostic skills remain an essential element, both with regards to identity, quality assurance of botanicals (both herbal medicines and supplements), and the discovery and development of new medicines. Over the years, the specific pharmacognostical tools have changed dramatically, and most recently, DNA-based techniques have become another element of our spectrum of scientific methods.

Relaciones ocultas a fines del siglo XVIII: la specimen florae americae meridionalis (1780) del Real Jardim Botânico da ajuda y los diseños científicos de la Real Expedición Botánica al virreinato peruano / Hidden relationships in late eighteen century: the specimen florae americae meridionalis (1780) of the Real Jardim Botânico da Ajuda and the scientific drawings of the Royal Botanical expedition to the Peru viceroyalty

Este artículo muestra que en las décadas finales del siglo XVIII, más allá de las relaciones diplomáticas y los conflictos militares entre Portugal y España, existieron importantes conexiones científicas, que han sido poco estudiadas. Teniendo como punto de partida la casi desconocida Specimen Florae Americae Meridionalis (1780), una obra botánica compuesta de cuatro volúmenes, producida en el Real Museu da Ajuda (Lisboa), exploraremos el interés que suscitó en los círculos de estudiosos y aficionados a la botánica en Lisboa la llegada de más de doscientos dibujos de plantas procedentes de la Real Expedición Botánica al Virreinato del Perú (1777-1788). Considerando las personalidades portuguesas, españolas e inglesas que estuvieron implicadas en la presencia de estos diseños en Portugal, recuperaremos algunas de las prácticas que posibilitaban en este período la circulación de conocimientos científicos y el adelanto de la botánica. En este sentido, este estudio pretende realizar una aportación novedosa a la Historia de la Botánica en Portugal y España y apuntar caminos para futuras investigaciones (AU)

This paper shows that in the final decades of the eighteenth century, beyond the diplomatic and military conflicts between Portugal and Spain, there were important scientific connections, which have been little studied. Having as a starting point the almost unknown Specimen Florae Americae Meridionalis (1780), a four volumes botanical work produced in Real Museu da Ajuda (Lisbon), we will explore the interest aroused in the circles of scholars and amateur botanists the arrival in Lisbon of over two hundred drawings of plants from the Royal Botanical Expedition to the Viceroyalty of Peru (1777-1788). Considering the Portuguese, Spanish and English personalities who were involved in the presence of these drawings in Portugal we will recover some of the practices that made possible in this period the circulation of scientific knowledge and the advancement of botany. In this sense, this study aims to make a novel contribution to the History of Botany in Portugal and Spain, and point paths for future research (AU)

Half a Century of Hawaiian Marine Natural Products.

The following review covers the primary literature concerning marine natural products isolated for the first time from organisms collected around the islands of Hawaii published in the 51-year period 1964 to July 2015. The review is divided into seven main sections based on major taxonomic groupings; algae, sponges, mollusks, miscellaneous invertebrates, cyanobacteria, bacteria, and fungi. The aim of the review is to discuss the compounds and information concerning their original biological activity and other potentially interesting properties. The majority of the 320 structures of isolated compounds are not shown directly in the review but are contained in the Supporting Information section in 22 figures, Figs. 1 S-22 S. The Supporting Information section also contains Table 1 S that has information relating to the taxonomic identification of the source organism of each compound, collection location of the source organism, a trivial or semi-systematic name for each compound, as well as its general structural class. The authors hope that this review will be the spawning ground for other reviews and the basis for a great deal more research into the marine life found in Hawaiian waters.

Natural product discovery: past, present, and future.

Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30-50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the "biosynthetic dark matter" as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.