Pseudo-natural products and natural product-inspired methods in chemical biology and drug discovery

Through evolution, nature has provided natural products (NPs) as a rich source of diverse bioactive material. Many drug discovery programs have used nature as an inspiration for the design of NP-like compound classes. These concepts are guided by the prevalidated biological relevance of NPs while going beyond the limitations of nature to produce chemical matter that could have unexpected or novel bioactivities. Herein, we discuss, compare, and highlight recent examples of NP-inspired methods with a focus on the pseudo-NP concept.     

Total in vitro biosynthesis of the nonribosomal macrolactone peptide valinomycin

Natural products are important because of their significant pharmaceutical properties such as antiviral, antimicrobial, and anticancer activity. Recent breakthroughs in DNA sequencing reveal that a great number of cryptic natural product biosynthetic gene clusters are encoded in microbial genomes, for example, those of Streptomyces species. However, it is still challenging to access compounds from these clusters because many source organisms are uncultivable or the genes are silent during laboratory cultivation. To address this challenge, we develop an efficient cell-free platform for the rapid, in vitro total biosynthesis of the nonribosomal peptide valinomycin as a model. We achieve this goal in two ways. First, we used a cell-free protein synthesis (CFPS) system to express the entire valinomycin biosynthetic gene cluster (>19 kb) in a single-pot reaction, giving rise to approximately 37 μg/L of valinomycin after optimization. Second, we coupled CFPS with cell-free metabolic engineering system by mixing two enzyme-enriched cell lysates to perform a two-stage biosynthesis. This strategy improved valinomycin production ~5000-fold to nearly 30 mg/L. We expect that cell-free biosynthetic systems will provide a new avenue to express, discover, and characterize natural product gene clusters of interest in vitro.     

Comparative toxicity,growth inhibitory and biochemical effects of terpenes and phenylpropenes on Spodoptera littoralis (Boisd.)

Eleven monoterpenes, phenylpropenes and sesquiterpenes were evaluated for their insecticidal and growth inhibitory activities against the second and fourth larval instars of Spodoptera littoralis. Among the tested compounds, 1,8-cineole revealed the highest fumigant toxicity against the 2nd and 4th larval instars with LC₅₀ values of 2.32 and 3.13 mg/L air, respectively. The monoterpenes, p-cymene, α-terpinene, (−)α-pinene and (−)-carvone were highly toxic to both larval stages as their LC₅₀ values ranged between 7.35 and 13.79 mg/L air against 2nd larval instar and between 14.66 and 32.02 mg/L air against 4th larval instar. In topical application assay against the 4th larval instar, (−)-carvone (LD₅₀ = 0.15 mg/larva) and cuminaldehyde (LD₅₀ = 0.27 mg/larva) were the most potent contact toxicants. In residual film assay, trans-cinnamaldehyde, (−)-citronellal and p-cymene showed the highest insecticidal activity against the 2nd larval instar, while α-terpinene and (−)-carvone were most effective compounds against the 4th larval instar. Moreover, the tested compounds caused strong growth reduction of both larval stages with growth inhibition higher than 80% in the 2nd larval instar and higher than 70% in the 4th larval instar. On the other hand, (−)-carvone, cuminaldehyde and (Z,E)-nerolidol showed pronounced inhibitory effects on acetylcholinesterase (AChE) and adenosine triphosphatases (ATPases) activity of S. littoralis larvae. Cuminaldehyde (IC₅₀ = 1.04 mM) and (Z,E)-nerolidol (IC₅₀ = 0.02 mM) caused the highest inhibition of AChE and ATPases, respectively. Taken together, the results indicate that monoterpenes, phenylpropenes and phenylpropenes could be used to develop new botanical insecticides for S. littoralis management.     

Egg parasitoids (Hymenoptera: Mymaridae) of Amrasca biguttula (Ishida) (Hemiptera: Cicadellidae) on Okinawa Island,a pest of okra in Japan

The fairyfly Anagrus (Anagrus) japonicus Sahad (Hymenoptera: Mymaridae) is identified for the first time as an egg parasitoid of the okra leafhopper Amrasca (Sundapteryx) biguttula (Ishida) (Hemiptera: Cicadellidae) on Okinawa Island, Japan. Amrasca biguttula is a serious pest of okra, Abelmoschus esculentus (L.) Moench (Malvaceae), both in Okinawa and Bonin Islands. Female of A. japonicus is redescribed, and its previously unknown male is described, based on the reared specimens from Okinawa. Prior to this study, host associations of A. japonicus were unknown. Another species of Mymaridae, Arescon enocki (Subba Rao and Kaur), also emerged from eggs of A. biguttula on okra in Okinawa, albeit in much smaller numbers.     

羌塘国家级自然保护区地表土壤冻结天数时空变化特征

利用1981—2018年羌塘自然保护区周边5个气象台站的地表逐日最低温度和平均气温资料,采用线性回归和Mann-Kendall非参数检验方法,分析了近38 a以及全球变暖1.5℃和2℃阈值时羌塘自然保护区地表土壤冻结天数的时空变化特征。结果表明:(1)近38 a近地表土壤冻结开始日期呈推迟趋势,变化率为7.72 d·10 a^-1,冻结终止日期以8.17d·10 a^-1的速率显著提早;冻结持续时间和冻结天数均呈显著缩短趋势,平均每10年分别缩短14.69和11.19 d;同时段内,自然保护区大部分土壤冻结参数的变化率均大于青藏高原。(2)在年代际变化上,自然保护区呈现土壤冻结开始日期推迟、冻结终止日期提前、冻结持续时间和冻结天数缩短的变化特征。(3)土壤冻结参数在21世纪初均发生了气候突变,较青藏高原土壤冻融时间的突变点偏晚。(4)在全球变暖1.5℃时,RCP4.5和RCP8.5情景下的自然保护区土壤冻结参数变化值相同,冻结开始日期推迟25 d,冻结终止日期提早22 d,冻结持续时间和冻结天数分别缩短46和28 d;变暖2.0℃时,RCP4.5和RCP8.5情景下的土壤冻结开始日期推迟35和33 d,冻结终止日期提早30和29 d,冻结持续时间减少64和62 d,冻结天数缩短40和39 d。     

Identification of vibsanin A analog as a novel HSP90 inhibitor

Vibsanin A is the first natural product isolated from Viburnum awabuki and has several biological activities. We have reported that a vibsanin A analog, obtained from process of total synthesis of vibsanin A, has anti-proliferative activity against human cancer cell lines. In this study, we evaluated anti-proliferative effect of the vibsanin A analogs against various human cancer cell lines and examined molecular target of the analog in human cells. Among the vibsanin A analogs, vibsanin A analog C (VAC) showed anti-proliferative effect against various cancer cell lines, and the anti-proliferative activity was strongest among the vibsanin A analogs. Additionally, VAC fluctuated amounts of HSP90-related proteins in cells and inhibited HSP90-mediated protein refolding of luciferase in vitro. These results suggest that the anti-proliferative activity of VAC is due to HSP90 inhibition, and VAC has a potential as novel anti-cancer drug as HSP90 inhibitor.     

三江源区生态系统和土壤保持服务对未来气候变化的响应特征

气候变化条件下的生态系统响应特征对生态系统服务的提升和生态环境保护具有重要意义。现有气候变化评估多以全球或区域大尺度研究为主,不适合局地小尺度。以2015年为基准,根据局地特征改进了综合顺序分类系统（CSCS）,模拟了未来不同温室气体排放模式下三江源地区自然植被分布,同时分析了植被覆盖度及土壤保持功能的时空变化。研究结果表明：①在2080年的不同排放情境下,三江源地区的降水和气温增长主要发生在生长季（5—9月）和半湿润地区,其中,高排放情境的增幅最大（42.21 mm和4.93℃）;②三江源地区潜在自然植被主要由草地转化为森林,植被覆盖度和土壤保持服务在不同排放情境下均呈现由西北向东南增加的趋势,与水热规律一致,其中高排放情境的增幅最大,低排放最小;③ 利用三江源地区原生裸地演替特点和多年NPP改进的CSCS模型,模拟精度提高了24%。研究成果为局地小尺度生态系统气候响应特征提供了必要的手段和规律认识。     

中国天然林资源保护工程综合评价指标体系与评估方法

天然林资源是国家重要的战略资源与生态资源,在维护国土生态安全、应对气候变化、保护生物多样性等方面发挥着不可替代的重要作用。作为覆盖范围最广、投资规模最大的天然林资源保护工程（简称天保工程）自2000年正式启动以来,对长江上游、黄河上中游地区以及东北、内蒙古、新疆、海南等重点国有林区的森林资源保护修复、区域生态环境改善及经济社会可持续发展等多方面都产生了巨大、深远影响。天保工程二期于2020年结束,全面定量评估天保工程的生态、经济和社会综合效益和国内外的巨大影响,可为全面推进我国天然林资源保护修复提供科技支撑,为后续政策修订提供决策依据。本文基于空间信息技术、样地调查、生态站观测、比较分析等手段,构建了适用于天保工程的综合评价指标体系与评估方法,涵盖森林资源、生态效益、社会经济效益、生态修复措施和政策设计5个方面,对全面贯彻落实国家生态文明战略和《天然林保护修复制度方案》具有重要的现实意义和深远历史意义,为开展全国性的重大生态工程评估提供借鉴和参考。     

Genomes of 12 fig wasps provide insights into the adaptation of pollinators to fig syconia

Figs and fig pollinators are one of the few classic textbook examples of obligate pollination mutualism. The specific dependence of fig pollinators on the relatively safe living environment with sufficient food sources in the enclosed fig syconia implies that they are vulnerable to habitat changes. However, there is still no extensive genomic evidence to reveal the evolutionary footprint of this long-term mutually beneficial symbiosis in fig pollinators. In fig syconia, there are also non-pollinator species. The non-pollinator species differ in their evolutionary and life histories from pollinators. We conducted comparative analyses on 11 newly sequenced fig wasp genomes and one previously published genome. The pollinators colonized the figs approximately 66.9 million years ago, consistent with the origin of host figs. Compared with nonpollinators, many more genes in pollinators were subject to relaxed selection. Seven genes were absent in pollinators in response to environmental stress and immune activation. Pollinators had more streamlined gene repertoires in the innate immune system, chemosensory toolbox, and detoxification system. Our results provide genomic evidence for the differentiation between pollinators and nonpollinators. The data suggest that owing to the long-term adaptation to the fig, some genes related to functions no longer required are absent in pollinators.     

Botanical candidates from Saudi Arabian flora as potential therapeutics for Plasmodium infection

Malaria is a lethal parasitic disease affecting over two hundred million people worldwide and kills almost half a million people per year. Until now, there is no curative treatment for this disease that has a substantial morbidity. The available chemotherapeutic agents are unable to completely control the infection with the continuous appearance of drug resistance. Consequently, the search for new therapeutic agents with high safety profiles and low side effects is of paramount importance. Several natural products have been investigated and proven to have antimalarial effects either in vivo or in vitro. A large number of plants have been studied globally for their antimalarial activities. However, studies that have been conducted in this field in Saudi Arabia are not enough. This article presents global and local research on the need for novel natural antimalarial agents with a particular emphasis on studies involving plants from Saudi Arabian flora.