Chem Shanghai Institute of Medicine cooperated to discover natural macrocycloxime-like compounds with anti-influenza virus H1N1 activity

The influenza virus seriously affects human life and health and poses a great threat
to the world's public health system.
During flu season, there are up to millions of severe cases each year, and about 250,000 to 500,000 people die
.
Influenza viruses have a complete replication cycle
of adsorption release.
Throughout the viral replication process, antiviral drugs
with different targets have been discovered for the virus itself and the host.
However, with the mutation of influenza virus, existing anti-influenza drugs are facing a severe drug resistance situation, and it is urgent to develop new skeleton molecules and promote the research and development of
anti-influenza virus drugs.

Natural products are a treasure trove of drug discovery, and they play a very important role
in target identification and lead discovery.
Nevertheless, natural products present challenges
such as low separations, complex total synthesis, and difficulty in molecular editing.
On the contrary, natural products have the characteristics of high availability, diverse structure and rich functions, which have attracted widespread attention
from medicinal chemists.
In particular, natural macrocyclic compounds, which are a class of cyclic compounds containing twelve or more atoms, have a special 3D conformation, appropriate rigidity and flexibility, not only enhance selectivity and affinity with target proteins, but also intervene in difficult targets, such as protein-protein interaction (PPI).

In the study of anti-influenza virus natural products, Yang Weibo's research group of Shanghai Institute of Materia Medica) based on the biomimetic modular strategy (Nat.
Commun.
2020, 11, 2151.
; J.
Am.
Chem.
Soc.
2020, 142, 9982-9992.
; Nat.
Commun.
2021, 12, 1304.
), developed Rh(III)-catalyzed bimolecular double-carbon-hydrogen bond-activated macrocyclization reaction
.
It is worth noting that this reaction mode uses the method of in-situ generation of guide groups, and highly chemically selectively achieves tandem amidation-alkylation, tandem amidation-alkenylation and tandem amidation-allyl macrocyclization
, respectively.
These results provide an effective tool
for the rapid and efficient construction of structurally diverse natural oxime-like macrocyclic libraries.

Recently, the research team conducted PMI analysis on the conformation of the molecule and found that the obtained natural oxime macrocyclic library contains a rare spherical conformation in addition to linear and planar conformations
.
Finally, the research team performed phenotypic screening on the natural oxime-like macrocyclic library, and the results showed that such compounds had activity against influenza virus H1N1 (among which the active latest compounds_IC50= 0.
57 μM, CC_{50> 100} μM, SI >176), and further, through the structure-activity relationship, it was found that the oxime group and α in the target molecule, β unsaturated groups are indispensable
for maintaining activity.
At non-cytotoxic concentrations, the lead compound has a good protective effect
against cytopathies caused by viruses.
At the same time, immunofluorescence experiments have shown that the target compound can significantly reduce the fluorescence intensity
of the nucleoprotein of the infected virus.
The results were published
online in Chem magazine on November 10.

Professor Weibo Yang, researcher Wei Huang, associate researcher Li Yang and Professor Kendall N.
Houk of the University of California, Los Angeles are co-corresponding authors
.
Researcher Zheng Mingyue and researcher Zuo Jianping of Shanghai Institute of Materia Medica, provided technical support
for this research.
Hao Wang, Zhongyu Li, Tongyu Bi, Xiangyang Chen and Jonathan J.
Wong, University of California, Los Angeles, are co-first authors
.
The research project was supported
by the National Natural Science Foundation of China NSFC (22171275), the Ministry of Science and Technology, the Chinese Academy of Sciences, the Shanghai Municipal Science and Technology Commission, and the US NSF.

Link to the paper:

Study of natural macrocycloxime-like compounds with anti-influenza virus H1N1 activity

(Contributed by: Yang Weibo Research Group)