Article
Chemistry, Medicinal
Sitanshu S. Singh, George Mattheolabakis, Xin Gu, Sita Withers, Achyut Dahal, Seetharama Jois
Summary: This study developed grafted peptides to inhibit protein-protein interactions of EGFR and HER2 in NSCLC, with SFTI-G5 showing promising antiproliferative activity. In vivo experiments demonstrated that SFTI-G5 could inhibit tumor growth and reduce EGFR dimerization, indicating its potential as a novel dual inhibitor in NSCLC.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Rachel Kerr, Julia A. Fairbairn, Andrew T. Merritt, Timothy D. H. Bugg
Summary: The study revealed that MraY protein is the target for bacteriophage, with antimicrobial activity shown by analogues and improved antibacterial activity demonstrated by alpha-helix peptidomimetic analogues. The compounds exhibited bacteriostatic and bacteriocidal mechanisms, suggesting the potential of multiple biological targets. The observed antimicrobial activity and MraY inhibition indicate that this site could be targeted by drug-like molecules.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Markus Falkenstein, David Reiner-Link, Aleksandra Zivkovic, Ian Gering, Dieter Willbold, Holger Stark
Summary: Researchers have designed disease-modifying ligands that target multiple pathways in Alzheimer's disease, both disabling protein-protein interactions and acting as cognitive enhancers at the H3R receptor. These synthesized compounds show low nanomolar affinities at H3R, with some demonstrating promising interactions with A beta monomers. The structure-activity relationships described provide new avenues for developing multi-target compounds with optimized profiles for AD treatment.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Abraham Akonnor, Masaki Makise, Akihiko Kuniyasu
Summary: A CXCR4-targeted antitumor peptidomimetic (CTCE-KLAK) was developed and showed cell-selective cytotoxicity against breast cancer cells and induced rapid necrotic cell death. In a mouse model, CTCE-KLAK significantly inhibited tumor growth and lung metastasis, highlighting its potential as a promising agent for treating triple-negative breast cancer.
Article
Chemistry, Multidisciplinary
Ting Wang, Zheng He, Cong-Shan Yuan, Zhen-Wei Deng, Fang Li, Xi-Guang Chen, Ya Liu
Summary: The study developed enzyme-responsive PVA-peptide conjugates (PPCs) to improve the blocking efficiency of immune checkpoints in tumor-specific T cells. The self-assembled PPC-1 nanoparticles were able to enter tumor environment and effectively interrupt the PD-1/PD-L1 interaction. By introducing IAP antagonists, the study also increased the infiltration of T cells in tumors, improving the biodistribution and accumulation of PD-L1 antagonists and achieving higher tumor growth inhibition efficiency.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Chemistry, Medicinal
Inhwan Bae, Daejin Kim, Jaeyul Choi, Jisook Kim, Minjeong Kim, Bokyung Park, Young Hoon Kim, Young Gil Ahn, Ha Hyung Kim, Dae Kyong Kim
Summary: The newly designed and synthesized bivalent analogue 27 showed significant increase in cellular activity and caused substantial tumor regressions in MDA-MB-231 xenograft model, indicating its promising potential as an effective anti-tumor agent.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Jun Chen, Taige Zhao, Fengming He, Yijing Zhong, Susu Wang, Ziqing Tang, Yingkun Qiu, Zhen Wu, Meijuan Fang
Summary: A novel RXR alpha ligand BPA-B9 was synthesized, which targets the pRXR alpha-PLK1 interaction and shows excellent anti-proliferative activity against MDA-MB-231 cells. BPA-B9 also exhibits better pharmacokinetics and significant anticancer efficacy in vivo with no considerable side effects.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Michael A. Harris, Tanmay M. Shekhar, Mark A. Miles, Carmelo Cerra, Christine J. Hawkins
Summary: Treatment with the Smac mimetic LCL161 can effectively inhibit and in some cases eliminate the growth of osteosarcoma pulmonary metastases. Lung metastases removed from treated mice remained sensitive to LCL161 in combination with TNF alpha ex vivo, indicating minimal acquired resistance to LCL161 treatment in surviving osteosarcoma cells and suggesting the involvement of tumor microenvironmental factors in the variation of responses to LCL161.
CLINICAL & EXPERIMENTAL METASTASIS
(2021)
Article
Biochemistry & Molecular Biology
Federica Cossu, Simone Camelliti, Daniele Lecis, Luca Sorrentino, Maria Teresa Majorini, Mario Milani, Eloise Mastrangelo
Summary: Inhibitors of apoptosis proteins (IAPs) are important targets in cancer research, and the compound FC2 has been identified as a potential lead compound for the development of new IAP-antagonists for cancer treatment. FC2 can disrupt pro-survival pathways in cancer cells and induce cancer cell death, showing promise for combination therapy with other agents.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Pharmacology & Pharmacy
Achyut Dahal, Pravin Parajuli, Sitanshu S. Singh, Leeza Shrestha, Jafrin Jobayer Sonju, Prajesh Shrestha, Ioulia Chatzistamou, Seetharama Jois
Summary: Protein-protein interactions (PPI) of co-stimulatory molecules CD2-CD58 play an important role in the early stage of the immune response. Increased expression of these co-stimulatory molecules has been observed in the synovial region of joints in rheumatoid arthritis (RA) patients. In this study, a peptidomimetic was designed to inhibit CD2-CD58 PPI by grafting a CD2 epitope region onto a sunflower trypsin inhibitor (SFTI) template structure. The peptidomimetic showed stability against trypsin cleavage and was able to slow down the progress of arthritis in a murine model. These findings suggest that functional group grafting in stable peptide templates can be used to design stable peptides for therapeutic purposes.
JOURNAL OF PHARMACOLOGICAL SCIENCES
(2022)
Article
Chemistry, Physical
Xiao-Yun Li, Ze-Yue Huang, Ya Niu, Zi-Heng Wang, Lan-Yi Hu, Ai-Min Bai, Yan-Jun Hu
Summary: The synthesis and characterization of an IAP antagonist analogue (IAPA) and its interaction with proteins were studied in this research. The results showed that the binding between IAPA and proteins occurred through a static process driven by hydrophobic force, specifically at site I of the proteins. Fluorescence spectroscopy and molecular docking were used to further validate the findings.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Chemistry, Multidisciplinary
Ashley E. Modell, Frank Marrone, Nihar R. Panigrahi, Yingkai Zhang, Paramjit S. Arora
Summary: Constrained peptides are a valuable source of ligands for protein surfaces, but their binding affinity is often limited. This study proposes the use of nonnatural side chains to enhance binding affinity by accessing unoccupied crevices on the receptor surface. The computational method, AlphaSpace, was used to predict peptide ligands for the KIX domain of the p300/CBP coactivator, and experimental screening was performed to fine-tune the nonnatural side chains. The combined computational-experimental approach offers a general framework for optimizing peptidomimetics as inhibitors of protein-protein interactions.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Pharmacology & Pharmacy
Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul Matthias Diderichsen, Huub Jan Kleijn, Andre Koenig, Xiaozhe Wang, Andreas Schroeder, Kosalaram Goteti, Karthik Venkatakrishnan
Summary: Xevinapant demonstrated efficacy in combination with chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Population PK/PD modeling suggested that the recommended phase III dose was 200 mg/day, which showed robust inhibition and similar plasma concentration associated with efficacy. Exposure-response analyses showed exposure-related increases in probabilities of locoregional control and overall response. The integration of all available data supports the selection of xevinapant 200 mg/day as the RP3D.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Chemistry, Multidisciplinary
Liting Wang, Qing Shen, Hongze Liao, Hao Fu, Qi Wang, Jian Yu, Wei Zhang, Chuanrong Chen, Yang Dong, Xupeng Yang, Qianqian Guo, Jiali Zhang, Jian Zhang, Wei Zhang, Houwen Lin, Yourong Duan
Summary: This study identifies a novel inhibitor of DR6/APP interaction as a promising anti-hematogenous metastatic agent, which exhibits strong binding potency and excellent pharmacokinetic properties. The compound efficiently protects vascular endothelial cells from necroptosis induced by tumor cells and demonstrates significant anti-hematogenous metastatic activity in multiple metastatic mouse models.
Article
Chemistry, Medicinal
Kumiko Tsuihiji, Eiji Honda, Kanehisa Kojoh, Shizue Katoh, Tomonori Taguri, Atsushi Yoshimori, Hajime Takashima
Summary: Currently, there is a rapid development of various pharmaceutical modalities, with a focus on targeting protein-protein interactions (PPIs). Cyclic peptides have gained attention as potential alternatives to antibody drugs due to their specificity and activity. However, they also present challenges such as oral availability and cell permeability. To overcome these difficulties, this study proposes a rational two-step strategy to design small-molecule compounds targeting PPIs. The strategy involves obtaining inhibitory cyclic peptides and converting them into small molecules using PepMetics(R) scaffolds. The researchers successfully generated small-molecule compounds with good inhibitory activity against CTLA-4. This approach is expected to be a useful method for designing small molecules targeting PPIs, even without structural information.
Article
Biochemistry & Molecular Biology
Jianwen A. Feng, Ignacio Aliagas, Philippe Bergeron, Jeff M. Blaney, Erin K. Bradley, Michael F. T. Koehler, Man-Ling Lee, Daniel F. Ortwine, Vickie Tsui, Johnny Wu, Alberto Gobbi
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2015)
Article
Microbiology
J. Hiroshi Morisaki, Peter A. Smith, Shailesh V. Date, Kimberly K. Kajihara, Chau Linda Truong, Zora Modrusan, Donghong Yan, Jing Kang, Min Xu, Ishita M. Shah, Robert Mintzer, Eric M. Kofoed, Tommy K. Cheung, David Arnott, Michael F. T. Koehler, Christopher E. Heise, Eric J. Brown, Man-Wah Tan, Wouter L. W. Hazenbosa
Article
Chemistry, Medicinal
Philippe Bergeron, Michael F. T. Koehler, Elizabeth M. Blackwood, Krista Bowman, Kevin Clark, Ron Firestein, James R. Kiefer, Klaus Maskos, Mark L. McCleland, Linda Orren, Sreemathy Ramaswamy, Laurent Salphati, Steve Schmidt, Elisabeth V. Schneider, Jiansheng Wu, Maureen Beresini
ACS MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Michael F. T. Koehler, Philippe Bergeron, Elizabeth M. Blackwood, Krista Bowman, Kevin R. Clark, Ron Firestein, James R. Kiefer, Klaus Maskos, Mark L. McCleland, Linda Orren, Laurent Salphati, Steve Schmidt, Elisabeth V. Schneider, Jiansheng Wu, Maureen H. Beresini
ACS MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Frederick Cohen, Philippe Bergeron, Elizabeth Blackwood, Krista K. Bowman, Huifen Chen, Antonio G. DiPasquale, Jennifer A. Epler, Michael F. T. Koehler, Kevin Lau, Cristina Lewis, Lichuan Liu, Cuong Q. Ly, Shiva Malek, Jim Nonomiya, Daniel F. Ortwine, Zhonghua Pei, Kirk D. Robarge, Steve Sideris, Lan Trinh, Tom Truong, Jiansheng Wu, Xianrui Zhao, Joseph P. Lyssikatos
JOURNAL OF MEDICINAL CHEMISTRY
(2011)
Article
Chemistry, Medicinal
Brad E. Sleebs, Peter E. Czabotar, Wayne J. Fairbrother, W. Douglas Fairlie, John A. Flygare, David C. S. Huang, Wilhelmus J. A. Kersten, Michael F. T. Koehler, Guillaume Lessene, Kym Lowes, John P. Parisot, Brian J. Smith, Morey L. Smith, Andrew J. Souers, Ian P. Street, Hong Yang, Jonathan B. Baell
JOURNAL OF MEDICINAL CHEMISTRY
(2011)
Article
Chemistry, Medicinal
Mark Zak, Rohan Mendonca, Mercedesz Balazs, Kathy Barrett, Philippe Bergeron, Wade S. Blair, Christine Chang, Gauri Deshmukh, Jason DeVoss, Peter S. Dragovich, Charles Eigenbrot, Nico Ghilardi, Paul Gibbons, Stefan Gradl, Chris Hamman, Emily J. Hanan, Eric Harstad, Peter R. Hewitt, Christopher A. Hurley, Tian Jin, Adam Johnson, Tony Johnson, Jane R. Kenny, Michael F. T. Koehler, Pawan Bir Kohli, Janusz J. Kulagowski, Sharada Labadie, Jiangpeng Liao, Marya Liimatta, Zhonghua Lin, Patrick J. Lupardus, Robert J. Maxey, Jeremy M. Murray, Rebecca Pulk, Madeleine Rodriguez, Scott Savage, Steven Shia, Micah Steffek, Savita Ubhayakar, Mark Ultsch, Anne van Abbema, Stuart I. Ward, Ling Xiao, Yisong Xiao
JOURNAL OF MEDICINAL CHEMISTRY
(2012)
Article
Chemistry, Medicinal
Michael F. T. Koehler, Philippe Bergeron, Elizabeth Blackwood, Krista K. Bowman, Yung-Hsiang Chen, Gauri Deshmukh, Xiao Ding, Jennifer Epler, Kevin Lau, Leslie Lee, Lichuan Liu, Cuong Ly, Shiva Malek, Jim Nonomiya, Jason Oeh, Daniel F. Ortwine, Deepak Sampath, Steve Sideris, Lan Trinh, Tom Truong, Jiansheng Wu, Zhonghua Pei, Joseph P. Lyssikatos
JOURNAL OF MEDICINAL CHEMISTRY
(2012)
Article
Chemistry, Medicinal
Mark Zak, Christopher A. Hurley, Stuart I. Ward, Philippe Bergeron, Kathy Barrett, Mercedesz Balazs, Wade S. Blair, Richard Bull, Paroma Chakravarty, Christine Chang, Peter Crackett, Gauri Deshmukh, Jason DeVoss, Peter S. Dragovich, Charles Eigenbrot, Charles Ellwood, Simon Gaines, Nico Ghilardi, Paul Gibbons, Stefan Gradl, Peter Gribling, Chris Hamman, Eric Harstad, Peter Hewitt, Adam Johnson, Tony Johnson, Jane R. Kenny, Michael F. T. Koehler, Pawan Bir Kohli, Sharada Labadie, Wyne P. Lee, Jiangpeng Liao, Marya Liimatta, Rohan Mendonca, Raman Narukulla, Rebecca Pulk, Austin Reeve, Scott Savage, Steven Shia, Micah Steffek, Savita Ubhayakar, Anne van Abbema, Ignacio Aliagas, Barbara Avitabile-Woo, Yisong Xiao, Jing Yang, Janusz J. Kulagowski
JOURNAL OF MEDICINAL CHEMISTRY
(2013)
Article
Chemistry, Medicinal
Anthony A. Estrada, Daniel G. Shore, Elizabeth Blackwood, Yung-Hsiang Chen, Gauri Deshmukh, Xiao Ding, Antonio G. DiPasquale, Jennifer A. Epler, Lori S. Friedman, Michael F. T. Koehler, Lichuan Liu, Shiva Malek, Jim Nonomiya, Daniel F. Ortwine, Zhonghua Pei, Steve Sideris, Frederic St-Jean, Lan Trinh, Tom Truong, Joseph P. Lyssikatos
JOURNAL OF MEDICINAL CHEMISTRY
(2013)
Article
Multidisciplinary Sciences
Peter A. Smith, Michael F. T. Koehler, Hany S. Girgis, Donghong Yan, Yongsheng Chen, Yuan Chen, James J. Crawford, Matthew R. Durk, Robert I. Higuchi, Jing Kang, Jeremy Murray, Prasuna Paraselli, Summer Park, Wilson Phung, John G. Quinn, Tucker C. Roberts, Lionel Rouge, Jacob B. Schwarz, Elizabeth Skippington, John Wai, Min Xu, Zhiyong Yu, Hua Zhang, Man-Wah Tan, Christopher E. Heise
Article
Multidisciplinary Sciences
Hoangdung Ho, Anh Miu, Mary Kate Alexander, Natalie K. Garcia, Angela Oh, Inna Zilberleyb, Mike Reichelt, Cary D. Austin, Christine Tam, Stephanie Shriver, Huiyong Hu, Sharada S. Labadie, Jun Liang, Lan Wang, Jian Wang, Yan Lu, Hans E. Purkey, John Quinn, Yvonne Franke, Kevin Clark, Maureen H. Beresini, Man-Wah Tan, Benjamin D. Sellers, Till Maurer, Michael F. T. Koehler, Aaron T. Wecksler, James R. Kiefer, Vishal Verma, Yiming Xu, Mireille Nishiyama, Jian Payandeh, Christopher M. Koth
Article
Chemistry, Medicinal
Zhonghua Pei, Elizabeth Blackwood, Lichuan Liu, Shiva Malek, Marcia Belvin, Michael F. T. Koehler, Daniel F. Ortwine, Huifen Chen, Frederick Cohen, Jane R. Kenny, Philippe Bergeron, Kevin Lau, Cuong Ly, Xianrui Zhao, Anthony A. Estrada, Tom Truong, Jennifer A. Epler, Jim Nonomiya, Lan Trinh, Steve Sideris, John Lesnick, Linda Bao, Ulka Vijapurkar, Sophie Mukadam, Suzanne Tay, Gauri Deshmukh, Yung-Hsiang Chen, Xiao Ding, Lori S. Friedman, Joseph P. Lyssikatos
ACS MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
Michael F. T. Koehler, Philippe Bergeron, Edna F. Choo, Kevin Lau, Chudi Ndubaku, Danette Dudley, Paul Gibbons, Brad E. Sleebs, Carl S. Rye, George Nikolakopoulos, Chinh Bui, Sanji Kulasegaram, Wilhelmus J. A. Kersten, Brian J. Smith, Peter E. Czabotar, Peter M. Colman, David C. S. Huang, Jonathan B. Baell, Keith G. Watson, Lisa Hasvold, Zhi-Fu Tao, Le Wang, Andrew J. Souers, Steven W. Elmore, John A. Flygare, Wayne J. Fairbrother, Guillaume Lessene
ACS MEDICINAL CHEMISTRY LETTERS
(2014)
Article
Chemistry, Medicinal
Zhi-Fu Tao, Lisa Hasvold, Le Wang, Xilu Wang, Andrew M. Petros, Chang H. Park, Erwin R. Boghaert, Nathaniel D. Catron, Jun Chen, Peter M. Colman, Peter E. Czabotar, Kurt Deshayes, Wayne J. Fairbrother, John A. Flygare, Sarah G. Hymowitz, Sha Jin, Russell A. Judge, Michael F. T. Koehler, Peter J. Kovar, Guillaume Lessene, Michael J. Mitten, Chudi O. Ndubaku, Paul Nimmer, Hans E. Purkey, Anatol Oleksijew, Darren C. Phillips, Brad E. Sleebs, Brian J. Smith, Morey L. Smith, Stephen K. Tahir, Keith G. Watson, Yu Xiao, John Xue, Haichao Zhang, Kerry Zobel, Saul H. Rosenberg, Chris Tse, Joel D. Leverson, Steven W. Elmore, Andrew J. Souers
ACS MEDICINAL CHEMISTRY LETTERS
(2014)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
