Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.

Terpenes extracted from marine sponges with antioxidant activity:a systematic review

Marine biodiversity has emerged as a very promising resource of bioactive compounds and secondary metabolites from different sea organisms.The sponge’s secondary metabolites demonstrated various bioactivities and potential pharmacological properties.This systematic review of the literature focuses on the advances achieved in the antioxidant potential of marine sponges in vitro.The review was performed in accordance with PRISMA guidelines.The main inclusion criterion for analysis was articles with identification of compounds from terpene classes that demonstrate antioxidant activity in vitro.Searching in three different databases,two hundred articles were selected.After screening abstracts,titles and evaluating for eligibility of manuscripts 14 articles were included.The most performed analyzes to detect antioxidant activity were scavenging activity 2,2-diphenyl-1-picrylhydrazyl(DPPH)and measurement of intracellular reactive oxygen species(ROS).It was possible to identify 17 compounds of the terpene class with pronounced antioxidant activity in vitro.Scientific evidence of the studies included in this review was accessed by the GRADE analysis.Terpenes play an important ecological role,moreover these molecules have a pharmaceutical and industrial application.

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

The intriguing chemistry and biology of sulfur-containing natural products from marine microorganisms(1987-2020)

Natural products derived from marine microorganisms have received great attention as a potential resource of new compound entities for drug discovery.The unique marine environment brings us a large group of sulfur-containing natural products with abundant biological functionality including antitumor,antibiotic,anti-inflammatory and antiviral activities.We reviewed all the 484 sulfur-containing natural products(non-sulfated)isolated from marine microorganisms,of which 59.9%are thioethers,29.8%are thiazole/thiazoline-containing compounds and 10.3%are sulfoxides,sulfones,thioesters and many others.A selection of 133 compounds was further discussed on their structure-activity relationships,mechanisms of action,biosynthesis,and druggability.This is the first systematic review on sulfur-containing natural products from marine microorganisms conducted from January 1987,when the first one was reported,to December 2020.

An overview of the marine natural products in clinical trials and on the market

The first marine natural products that served as leads or scaffolds for medicines were discovered in the middle of last century:the arabinosyl glycosides from the marine sponge Tectitethya crypta.Synthesis and modifications of the natural molecules generated antiviral and antileukemic drugs developed in the 1970’s and in the following decades,including the first effective treatment against HIV infection.With the improvement of techniques for the elucidation of chemical structure of the molecules,as well as chemical synthesis,especially from the 1990’s,there was an increase in the number of bioactive natural products characterized from marine organisms.New chemical structures with high specificity towards molecular targets in cells allowed the development of new drugs with indication for the treatment of several illnesses,from cancer to new antibiotics,and even neurological disorders.Currently there are at least 13 molecules derived from marine natural products on advanced clinical trials,and nine were approved to be used as medicines.Considering that in the past eight years,more than 1000 new compounds from marine organisms were described,per year,the expectation is that many more drugs will be derived from marine natural products in a near future.

Metabolites from marine invertebrates and their symbiotic microorganisms: molecular diversity discovery, mining, and application

Metabolites from marine organisms have proven to be a rich source for the discovery of multiple potent bioactive moleculeswith diverse structures. In recent years, we initiated a program to investigate the diversity of the secondary metabolites frommarine invertebrates and their symbiotic microorganisms collected from the South China Sea. In this review, representativecases are summarized focusing on molecular diversity, mining, and application of natural products from these marineorganisms. To provide a comprehensive introduction to the field of marine natural products, we highlight typical moleculesincluding their structures, chemical synthesis, bioactivities and mechanisms, structure-activity relationships as well as biogenesis. The mining of marine-derived microorganisms to produce novel secondary metabolites is also discussed through theOSMAC strategy and via partial chemical epigenetic modification. A broad prospectus has revealed a plethora of bioactivenatural products with novel structures from marine organisms, especially from soft corals, gorgonians, sponges, and theirsymbiotic fungi and bacteria.

Discovery of a natural small‑molecule AMP‑activated kinase activator that alleviates nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis(NASH)is a primary cause of cirrhosis and hepatocellular carcinoma.Unfortunately,there is no approved drug treatment for NASH.AMP-activated kinase(AMPK)is an important metabolic sensor and whole-body regulator.It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity,type 2 diabetes and NASH.In this study,we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator,candidusin A(CHNQD-0803).Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a K_(D) value of 4.728×10^(-8) M and activates AMPK at both molecular and intracellular levels.We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition,LPS-stimulated infammation,TGF-β-induced fbrosis cell models and the MCD-induced mouse model of NASH.The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition,negatively regulated the NF-κB-TNFαinfammatory axis to suppress infammation,and ameliorated liver injury and fbrosis.These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.

Discovery and development of synthetic tricyclic pyrroloquinone （TPQ） alkaloid analogs for human cancer therapy

Natural products and their derivatives repre- sent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthesis and evaluation of three synthetic tricyclic pyrroloquinone （TPQ） alkaloid analogs as cancer therapeutic agents. Chemical synthesis of these compounds （BA-TPQ, TBA-TPQ, and TCBA-TPQ） has been accomplished and the mechanisms of action （MOA） and structure-activity relationships （SAR） have been investigated. In the past, the complexity of chemical synthesis and the lack of well-defined MOA have dampened the enthusiasm for the development of some makaluvamines. Recent discovery of novel molecular targets for these alkaloids （unrelated to inhibition of Topoisomerase II） warrant further consideration as clinical candidates in the future. In addition to the establishment of novel synthetic approaches and demonstration of in vitro and in vivo anticancer activities, we have successfully demonstrated that these makaluvamines attack several key molecular targets, including the MDM2-p53 pathway, providing ample opportunities of modulating the compound structure based on SAR and the use of such compounds in combination therapy in the future.

Antibacterial and bioiflm inhibitory activities of bacteria associated with polychaetes

Objective:To study the antibacterial and antibiofilm activities expressed by epibiotic bacteria associated with the polychaetes Platynereis dumerilii and Syllis sp.Methods:A total of 32 cultivable bacterial strains were isolated from the two polychaete species.The crude extracts were tested for antibacterial activity and biofilm inhibitory activity against pathogenic and biofilm-forming bacterial strains.Extracts of the strains which showed strong activity were analyzed by thin-layer chromatography(TLC)and the bacterial strains were identified based on 16S rRNA gene sequencing.Results:Extracts of 13 bacterial strains showed inhibitory activity against pathogenic and biofilm-forming bacteria.The crude extracts also affected the synthesis of extracellular polymeric substances and cell surface hydrophobicity of the Alteromonas sp.isolated from marine biofilm.The adhesion of Alteromonas sp.on glass surface showed significant variation between surface-associated bacterial crude extract treatment and control groups.Among the 13 bacteria,two strains PA8 and PA19 were further analyzed for bioactive fractions.Thinlayer chromatography indicated the presence of a single active fraction in the crude extract of both the bacterial strains.The epibiotic bacterial strains P8 and P19 were identified as Exiguobacterium sp.and Actinobacterium sp.respectively based on 16S rRNA gene sequencing.Conclusions:The present study indicates that bacteria associated with marine invertebrates inhabiting the coastal waters could be used as a potential source for the isolation of bioactive metabolites.