Hedgehog inhibitors from Artocarpus communis and Hyptis suaveolens

Arai, Midori A.; Uchida, Kyoko; Sadhu, Samir Kumar; Ahmed, Firoj; Koyano, Takashi; Kowithayakorn, Thaworn; Ishibashi, Masami

doi:10.1016/j.bmc.2015.06.058

Cited by 10 publications

(3 citation statements)

References 30 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, four compounds generated OD 600 of >90%. The four compounds were physalin H isolated from Solanum nigrum ( Arai et al, 2014 ) ( Figure 1A ), lasidiol p -methoxybenzoate isolated from Xanthium strumarium ( Karmakar et al, 2015 ), ovatodiolide isolated from Hyptis suaveolens ( Arai et al, 2015 ), and ceanothic acid isolated from Zizyphus cambodiana ( Arai et al, 2008 ), suggesting that these compounds can suppress Agr-QS in MRSA without repressing bacterial growth.…”

Section: Resultsmentioning

confidence: 99%

Physalin H, physalin B, and isophysalin B suppress the quorum-sensing function of Staphylococcus aureus by binding to AgrA

Yamaguchi,

Manome,

Hara

et al. 2024

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

The virulence of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), depends on the expression of toxins and virulence factors controlled by the quorum-sensing (QS) system, encoded on the virulence accessory gene regulator (agr) locus. The aim of this study was to identify a phytochemical that inhibits Agr-QS function and to elucidate its mechanism. We screened 577 compounds and identified physalin H, physalin B, and isophysalin B—–phytochemicals belonging to physalins found in plants of the Solanaceae family—–as novel Agr-QS modulators. Biological analyses and in vitro protein–DNA binding assays suggested that these physalins suppress gene expression related to the Agr-QS system by inhibiting binding of the key response regulator AgrA to the agr promoters, reducing the function of hemolytic toxins downstream of these genes in MRSA. Furthermore, although physalin F suppressed gene expression in the Agr-QS system, its anti-hemolytic activity was lower than that of physalins H, B, and isophysalin B. Conversely, five physalins isolated from the same plant with the ability to suppress Agr-QS did not reduce bacterial Agr-QS activity but inhibited AgrA binding to DNA in vitro. A docking simulation revealed that physalin interacts with the DNA-binding site of AgrA in three docking states. The carbonyl oxygens at C-1 and C-18 of physalins, which can suppress Agr-QS, were directed to residues N201 and R198 of AgrA, respectively, whereas these carbonyl oxygens of physalins, without Agr-QS suppression activity, were oriented in different directions. Next, 100-ns molecular dynamics simulations revealed that the hydrogen bond formed between the carbonyl oxygen at C-15 of physalins and L186 of AgrA functions as an anchor, sustaining the interaction between the carbonyl oxygen at C-1 of physalins and N201 of AgrA. Thus, these results suggest that physalin H, physalin B, and isophysalin B inhibit the interaction of AgrA with the agr promoters by binding to the DNA-binding site of AgrA, suppressing the Agr-QS function of S. aureus. Physalins that suppress the Agr-QS function are proposed as potential lead compounds in the anti-virulence strategy for MRSA infections.

show abstract

Section: Resultsmentioning

confidence: 99%

Physalin H, physalin B, and isophysalin B suppress the quorum-sensing function of Staphylococcus aureus by binding to AgrA

Yamaguchi,

Manome,

Hara

et al. 2024

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Physalin H ( 180 ) isolated from Solanum nigrum inhibited the Gli1‐mediated transcription with an IC 50 value of 0.70 μM. Further mechanistic studies showed that 180 was able to disrupt the binding of Gli1 to its DNA‐binding domain (Figure ).…”

Section: Hh Signaling Pathway Inhibitorsmentioning

confidence: 99%

Strategies to target the Hedgehog signaling pathway for cancer therapy

Xin

Cruz

et al. 2018

Medicinal Research Reviews

100

View full text Add to dashboard Cite

Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.

show abstract

“…The methanolic extract of leaves of Artocarpus communis (Moraceae) and methanolic extract of flowers of Hyptis suaveolens (Lamiaceae) were screened for possible Hh inhibitory potential by Arai et al 160 Among the isolated compounds, 4 α -hydroperoxy-5-enovatodiolids 19a , 4-methylene-5 β -hydroperoxyovatodiolide 19b , and ovatodiolide 19c (Figure 19) possessed potent Hh signal inhibitory activity. These compounds also showed high cytotoxicity against PANC1 and DU145 cancer cells, which have active Hh signal.…”

Section: Recent Advances In Design Of Hh Pathway Inhibitorsmentioning

confidence: 99%

Design of Hedgehog pathway inhibitors for cancer treatment

Bariwal

Kumar

Dong

et al. 2018

Medicinal Research Reviews

View full text Add to dashboard Cite

Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.

show abstract

Hedgehog inhibitors from Artocarpus communis and Hyptis suaveolens

Cited by 10 publications

References 30 publications

Physalin H, physalin B, and isophysalin B suppress the quorum-sensing function of Staphylococcus aureus by binding to AgrA

Physalin H, physalin B, and isophysalin B suppress the quorum-sensing function of Staphylococcus aureus by binding to AgrA

Strategies to target the Hedgehog signaling pathway for cancer therapy

Design of Hedgehog pathway inhibitors for cancer treatment

Contact Info

Product

Resources

About