The molecular basis of how Pradimicin A binds to viral N-glycan, a potential SARS-CoV-2
entry inhibitor
HIV, Ebola and most recently, COVID-19 viruses have had an enormous impact on our societies
world-wide. All these viruses are ‘enveloped viruses,’ viruses that have an exterior envelope thatsurrounds them largely composed of its host’s cells. This envelope increases the virus’s ability tohide from their host’s immune system and to access the host’s cells. It also, however, gives
researchers a target, an opportunity to interrupt viral transmission.
Japanese researchers have been working on the issue of halting viral transmission in these typesof viruses. “The development of vaccines and antiviral drugs against COVID-19 has successfully
reduced the risk of death, but complete suppression of viral transmission is still challenging.
Under such circumstances, we evaluated the potential of naturally occurring pradimicin A (PRMA) as a new anti-SARS-CoV-2 drug that suppresses SARS-CoV-2 transmission,” said Yu
Nakagawa, the lead author on the paper and an associate professor in the Institute for Glyco-core
Research (iGCORE) at Nagoya University, Nagoya, Japan.
There is strong evidence that PRM-A is a viral entry inhibitor, in other words it stops viruses
from entering a host’s cells. It does this by binding to N-glycans, which are found on the surfaceof several types of enveloped viruses including the SARS-CoV-2 virus. However, there is still
little known about how exactly PRM-A binds to the viral N-glycans.
Their research was published in Bioorganic & Medicinal Chemistry on May 1.
To infect a cell, a virus’s envelope uses specific receptors on its surface called spike proteins—which are usually glycoproteins, meaning carbohydrates, specifically sugar (oligosaccharides)
attached to proteins—to bind to the cellular membrane of a host’s cell, causing a conformationalchange in the cell membrane which allows the virus to enter the cells. Once there, it uses thecell’s resources to replicate its own genome, safe from the host’s immune system.
Initially researchers looking at interrupting viral transmission focused on lectins, carbohydratebinding proteins that are derived from plants or bacteria, which showed strong promise as a viralentry inhibitor. They bind with the viruses’ glycoproteins and stop its advance into a cell.
However, they are often expensive, easily targeted by the host’s immune system, and may be
toxic to the host’s cells. Lectin mimics have many of the carbohydrate-binding ability of thelectin without the expensive and dangerous side effects.
The Japanese team looked at PRM-A, a naturally occurring lectin mimic. It has shown promise
as a viral entry inhibitor as there is evidence it binds to the N-glycans of the viruses’ envelope
glycoproteins. To determine the molecular basis of the binding, they used molecular modelling
and ran binding assays which measure the reactions between PRM-A and N-glycans as theybind. They also carried out in vitro experiments to test PRM-A’s ability to inhibit SARS-CoV-2.
They found that PRM-A binds selectively to branched oligomannose structures found in highmannose-type and hybrid-type N-glycans on viral spike proteins. Mannose is the specific sugar
found in these N-glycans. They also found that PRM-A did inhibit the infectivity of SARS-CoVPage 1 of 4

2. In fact, the inhibition occurred through the interaction between the PRM-A and the branchedoligomannose-containing N-glycans.
“We demonstrated for the first time that PRM-A can inhibit SARS-CoV-2 infection by binding
to viral glycans. It is also noteworthy that PRM-A was found to bind preferentially to branchedoligomannose motifs of viral glycans via simultaneous recognition of two terminal mannose
residues. This finding provides essential information needed to understand the antiviralmechanism of PRM-A,” said Nakagawa.
Nakagawa and their team are already busy working on the next step in their research. “Ourultimate goal is to develop anti-SARS-CoV-2 drugs based on PRM-A. The glycan-targeted
antiviral action of PRM-A has never been observed in major classes of the existing
chemotherapeutics, underscoring its potential as a promising lead for antiviral drugs with thenovel mode of action. Especially, considering that glycan structures are hardly changed by viralmutation, we expect that PRM-A-based antiviral drugs would be effective against mutatedviruses. Toward this goal, we are now examining in vivo antiviral activity of PRM-A using
hamsters, and also developing PRM-A derivatives that are more suitable for therapeuticapplications,” said Nakagawa.
Other contributors include Masato Fujii, Nanaka Ito and Makoto Ojika of the Department ofApplied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan. Dai Akase of the Graduate School of Advanced
Science and Engineering, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima,Hiroshima 739-8526, Japan. Misako Aida of the Office of Research and Academia-GovernmentCommunity Collaboration, Hiroshima University, 1-3-2 Kagamiyama, Higashi-Hiroshima,Hiroshima 739-8511, Japan. Takaaki Kinoshita, Yasuteru Sakurai and Jiro Yasuda of theDepartment of Emerging Infectious Diseases, National Research Center for the Control andPrevention of Infectious Diseases (CCPID), Nagasaki University, 1-12-4 Sakamoto, Nagasaki
852-8523, Japan. Yasuhiro Igarashi of the Biotechnology Research Center, Toyama PrefecturalUniversity, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan. Yukishige Ito of the Graduate
School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043,
Japan.
This work was partly supported by JSPS KAKENHI grant (to Y.N.), the Cooperative Research
Project Program of the National Research Center for the Control and Prevention of Infectious
Diseases, Nagasaki University (to Y.N.), the Agricultural Chemical Research grant from theJapan Society for Bioscience, Biotechnology, and Agrochemistry (to Y.N.). Candida rugosa AJ
14513 was provided by Ajinomoto Co., Inc. (Kanagawa, Japan). SARS-CoV-2 strain,
JPN/NGS/SC-1/2020 (GISAID Accession ID: EPI_ISL_481254) was provided by Nagasaki
University through the National BioResource Project (Human pathogenic viruses) of MEXT,
Japan.
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Suggested EurekAlert! Summary:HIV, Ebola and most recently, COVID-19 viruses have had an enormous impact on our societies
world-wide. All these viruses are ‘enveloped viruses,’ viruses that have an exterior envelope thatsurrounds them largely composed of its host’s cells. This envelope increases the virus’s ability tohide from their host’s immune system and to access the host’s cells. It also, however, gives
researchers a target, an opportunity to interrupt viral transmission.

Primary Keyword:
Health and medicine
Secondary Keyword:
Infectious diseases,
Antiviral activity,
Bioactive compounds,
Drug development,
Drug targets,
Medicinal chemistry

Image title: Pradimicin A binding to the branched oligomannose structure and the results of the in vitro experiments on viral
infection of SARS-CoV-2 when exposed to PRM-A.
Image caption: An illustration of the PRM-A molecule and the branched oligomannose structure found in N-glycans and how
they bind with a graphic representation of the resultant decrease in the relative infectivity of the SARS-CoV-2 virus when
exposed to PRM-A.
Image credit: Yu Nakagawa, Nagoya University
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of news
coverage of this paper only.

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新型コロナウイルスの感染を抑制する天然物質を特定～多様な変異株に有効な革新的抗ウイルス薬の開発に期待～【本研究のポイント】
・糖の一種であるマンノース(Man)に結合する天然物・プラディミシン A が新型コロナウイルス (SARS-CoV-2) の感染を抑制することを発見した。
・プラディミシン A が SARS-CoV-2 表面に存在する糖鎖に結合できることを確認するとともに、プラディミシン A とウイルス糖鎖との結合メカニズムの概要を明らかにした。
・糖鎖構造はウイルスの変異によって変化しにくいことから、プラディミシン A を基にして様々な変異株に有効な革新的抗 SARS-CoV-2 薬を開発できる可能性がある。
【研究概要】
名古屋大学糖鎖生命コア研究所の中川 優 准教授、長崎大学高度感染症研究センターの安田 二朗 教授、木下 貴明 助教、櫻井 康晃 助教、広島大学の相田 美砂子 特命教授、赤瀬 大 助教、富山県立大学の五十嵐 康弘 教授、大阪大学大学院理学研究科の伊藤 幸
成 特任教授らの研究グループは、放線菌が生産する天然物・プラディミシン A が新型コロナウイルスの表面に存在する糖鎖に結合してその感染を抑制することを新たに発見しました。
近年、新型コロナウイルス (SARS-CoV-2) の表面には多数の糖鎖が付加されていることが明らかにされています。本研究では、SARS-CoV-2 が有する糖鎖にマンノースが多数含まれていることに着目し、マンノース結合活性を有するプラディミシン A が SARSCoV-2 の糖鎖に結合して細胞レベルでウイルス感染を抑制することを見出しました。さらに、プラディミシン A とウイルス糖鎖との結合メカニズムの概要も明らかにしました。糖鎖構造はウイルスの変異によって変化しにくいことから、これらの知見を基にして様々な変異株に有効な革新的抗 SARS-CoV-2 薬が開発されることが期待されます。
本研究成果は、2024 年 4 月 18 日付化学誌「Bioorganic & MedicinalChemistry」にオンラインで掲載されました。
【研究の詳細】https://www.nagoyau.ac.jp/researchinfo/result/upload_images/20240703_igcore.pdf

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