Acta Pharmaceutica Sinica B: PROTAC technology as a new tool for the identification of diterpenoid targets

Proteolytic targeting chimeras (PROTAC) is a novel method
for selective degradation of target proteins using endogenous proteasomes.
Since PROTAC can degrade target proteins without high affinity, it is natural to speculate that this technique could be used to identify targets for natural products
.

Although a recent study reported the use of PROTACs to explore unknown non-kinase targets for a multi-kinase inhibitor sorafenib, whether PROTACs can be used to find potential targets for natural products remains unexplored
.

Image source: https://doi.
org/10.
1016/j.
apsb.
2022.
07.
007

Recently, researchers from Shenyang Pharmaceutical University published an article entitled "PROTAC technology as a novel tool to identify the target of lathyrane diterpenoids" in Acta Pharmaceutica Sinica B, which summarizes PROTAC technology as a new tool
for identifying diterpenoid targets.

In previous studies, researchers obtained several new lysine diterpenoids from Euphorbia and demonstrated that they have strong anti-inflammatory activity
at low molar levels and low toxicity 。 Among them, (2S, 3S, 4S, 5R, 9S, 11R, 15R)-15-acetoxy-3cinnamoyloxy-5-hydroxyl-14-oxolathyra-6(17), 12E-diene (ZCY001) has the strongest anti-lipopolysaccharide-stimulated NO release activity, and its IC50 value is 3.
0±1.
1 mm o l/L, but its exact target and anti-inflammatory mechanism still need further study
。

V-MAF Aponeural fibrosarcoma oncogene homologous F (MAFF) belongs to the small MAFS family of proteins, which also includes MAFG and MAFK, and is a basic region leucine zipper (BZIP) transcription factor
lacking trans-activating domains.
SMAF is an essential partner for CNC proteins including nuclear factor-erythroid 2-p45 correlated factor 2 (Nrf2), which activates target genes involved in antioxidant responses in a positive transcriptional manner, while homodimers of sMAF inhibit this activation
by competitively binding to mare or are.

In this paper, the researchers selected LaTIl, the most active diterpenoid compound ZCY-001 in the Rhineland, as the core skeleton structure, and synthesized a PROTAC molecule (ZCY-PROTAC) to identify its target
。 The investigators determined that MAFf was the target of LATYIL and (2S,3S,4R,5R,7R,9S,11R,15R)-5,15diacetoxy-3-benzoyloxy-7-hydroxyl-14-oxolathyra-6(17),12Ediene,ZCY020), which is a similar LATHRAN diterpenoid.

These results show that PROTAC technology is a promising new method
for target identification of natural products.

Maff is the target of Latril and ZCY020

Image source: https://doi.
org/10.
1016/j.
apsb.
2022.
07.
007

In summary, the researchers creatively used PROTAC technology combined with quantitative proteomics to observe the changes before and after proteomics and determined that MAFF is the key target protein of lathyrane diterpenoids
.

On this basis, the researchers verified that lathyrane diterpenoids ZCY020 exert anti-inflammatory effects through the MAF-nrf2 pathway by targeting MAFF in lps-induced RAW264.
7 macrophages and ALI mice, indicating that the PROTAC probe binding quantitative proteomics method, which the researchers call targeted degradomics, can be used as a novel and valuable complementary method for natural product and other drug target identification, and deserves further application and research
。 (Biovalley Bioon.
com)

References

Yanli Wu et al.
PROTAC technology as a novel tool to identify the target of lathyrane diterpenoids.
Acta Pharm Sin B.
2022 Nov; 12(11):4262-4265.
doi: 10.
1016/j.
apsb.
2022.
07.
007.