DNA G-Quadruplexes as Targets for Natural Product Drug Discovery

DNA guanine(G)-quadruplexes(G4s)are unique secondary structures formed by two or more stacked Gtetrads in G-rich DNA sequences.These structures have been found to play a crucial role in highly transcribed genes,especially in cancer-related oncogenes,making them attractive targets for cancer therapeutics.Significantly,targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins,such as MYC,BCL2,KRAS,and EGFR.Natural products have long been an important source of drug discovery,particularly in the fields of cancer and infectious diseases.Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs.Numerous DNA G4s,such as MYC-G4,BCL2-G4,KRAS-G4,PDGFR-b-G4,VEGF-G4,and telomeric-G4,have been identified as potential targets of natural products,including berberine,telomestatin,quindoline,sanguinarine,isaindigotone,and many others.Herein,we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders,focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature.We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.

65% cover is the sustainable vegetation threshold on the Loess Plateau

Global temperatures will continue to increase in the future.The∼640,000-km2 Loess Plateau(LP)is a typical arid and semi-arid region in China.Similar regions cover∼41%of the Earth,and its soils are some of the most severely eroded anywhere in the world.It is very important to understand the vegetation change and its ecological threshold under climate change on the LP for the sustainable development in the Yellow River Basin.However,little is known about how vegetation on the LP will respond to climate change and what is the sustainable threshold level of vegetation cover on the LP.Here we show that the temperature on the LP has risen 0.27°C per decade over the past 50 years,a rate that is 30%higher than the average warming rate across China.During historical times,vegetation change was regulated by environmental factors and anthropogenic activities.Vegetation coverage was about 53%on the LP from the Xia Dynasty to the Spring and Autumn and Warring States period.Over the past 70 years,however,the environment has gradually improved and the vegetation cover had increased to∼65%by 2021.We forecast future changes of vegetation cover on the LP in 2030s,in 2050s and in 2070s using SDM(Species Distribution Model)under Low-emission scenarios,Medium-emission scenarios and High-emission scenarios.An average value of vegetation cover under the three emission scenarios will be 64.67%,62.70%and 61.47%,respectively.According to the historical record and SDM forecasts,the threshold level of vegetation cover on the LP is estimated to be 53-65%.Currently,vegetation cover on the LP has increased to the upper limit of the threshold value(∼65%).We conclude that the risk of ecosystem collapse on the LP will increase with further temperature increases once the vegetated area and density exceed the threshold value.It is urgent to adopt sustainable strategies such as stopping expanding vegetation area and scientifically optimizing the vegetation structure on the LP to improve the ecological sustainability of the Yellow River Basin.

Macleayine,a new alkaloid from Madeaya cordata

Macleayine （1）, a new natural occurring alkaloid with a unique spiro [furanone-piperidinedione] framework, was isolated from the aerial parts ofMacleaya cordata. Its unusual structure was established by extensive spectroscopic analyses, computer-assisted structure elucidation software （ACD/Structure Elucidator）, quantum chemistry calculations and ECD calculation. The result of virtual molecular docking predicted the compound can enhance the effects of insulin, and may be used to treat tvpe II diabetes.