Article
Multidisciplinary Sciences
Manish Gupta, Alexander J. Pak, Gregory A. Voth
Summary: Researchers use molecular dynamics simulations to reveal the molecular mechanism of HIV-1 capsid formation, including the role of IP6. This study shows that IP6 initially promotes curvature generation by trapping pentameric defects and shifts the assembly behavior towards kinetically favored outcomes. Additionally, IP6 can stabilize metastable capsid intermediates and induce structural pleomorphism in mature capsids.
Article
Immunology
Anabela C. P. Picton, Maria Paximadis, Gemma W. Koor, Avani Bharuthram, Sharon Shalekoff, Ria Lassauniere, Prudence Ive, Caroline T. Tiemessen
Summary: Our study compared black South African HIV-1 controllers and uninfected healthy controls in terms of lymphocyte and monocyte CCR5 expression, immune activation, and PBMC mitogen-induced chemokine/cytokine production. Despite higher frequencies of activated T cells, controllers had significantly lower CCR5 density in T cell populations, particularly in those with higher viral loads. This suggests a possible genetic predisposition to lower CCR5 expression in individuals who naturally control HIV-1.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Immunology
Hager Mohamed, Theodore Gurrola, Rachel Berman, Mackenzie Collins, Ilker K. Sariyer, Michael R. Nonnemacher, Brian Wigdahl
Summary: HIV-1 infection is a global health burden, and current drug therapies face challenges. Novel anti-HIV-1 therapies targeting CCR5 have shown promise in preventing infection and are included in gene editing techniques, CCR5 blockade using antibodies or antagonists, or combinations of both.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Na Qu, Yachen Ying, Jinshan Qin, Antony K. Chen
Summary: In this study, self-assembled RNA nanostructures were developed to inhibit HIV-1 virus assembly, providing new avenues for RNA-based therapy.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Virology
Grigoriy Lerner, Nicholas Weaver, Boris Anokhin, Paul Spearman
Summary: This review provides an overview of the HIV-1 assembly process, highlighting recent advances in the field and identifying areas for future investigation.
Article
Immunology
Yerkezhan Amerzhanova, Luca Vangelista
Summary: This perspective provides an overview of CCR5 as a central molecular determinant and its potential therapeutic applications. The study focuses on CCR5 antagonism and its impact on receptor-ligand interactions. The analysis of CCL5 mutants reveals the potential for enhanced anti-HIV-1 activity. Furthermore, the exploration of strategies such as improving CCR5 interaction in regions distal to the chemokine N-terminus and developing allosteric antagonists opens up new possibilities for CCR5 blockade.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Dang-Nghiem Vo, Nicolas Leventoux, Mauricio Campos-Mora, Sandrine Gimenez, Pierre Corbeau, Martin Villalba
Summary: NK cells play a critical role in the antiviral immune response against HIV-1. Impaired NK cell activity is observed in HIV-1 patients, with alterations in NK cell subsets and the emergence of memory NK cells. NK cells can acquire CCR5 and CXCR4 through trogocytosis from T cells, but not CD4. HIV-1 patients exhibit distinct NK cell clusters, with increased expression of CXCR4 and CCR5 in viremic patients. Degranulation and trogocytosis may be linked in HIV-1 infection.
Article
Biochemistry & Molecular Biology
Alexei A. Adzhubei, Amol Kulkarni, Anna P. Tolstova, Anastasia A. Anashkina, Dmitri Sviridov, Alexander A. Makarov, Michael I. Bukrinsky
Summary: HIV-1 infection impairs cellular cholesterol efflux through downregulation of the cholesterol transporter ABCA1, with potential implications for metabolic co-morbidities. Inhibitors targeting the Nef:ABCA1 interaction may offer a promising approach to attenuate HIV-associated co-morbidities.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Chemistry, Multidisciplinary
Alexander J. Pak, Manish Gupta, Mark Yeager, Gregory A. Voth
Summary: A recent study using coarse-grained molecular dynamics simulations and free energy calculations reveals that inositol hexakisphosphate (IP6) plays an important role as an assembly accelerant for the formation of immature HIV-1 virions. IP6 promotes curvature generation and the development of fissure-like defects in the viral lattice. These findings highlight the significance of IP6 in viral morphogenesis and virus-like particle technologies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Immunology
Xiaoyan Hu, Yi Feng, Kang Li, Yueyang Yu, Abdur Rashid, Hui Xing, Yuhua Ruan, Lingling Lu, Min Wei, Yiming Shao
Summary: CRF07_BC is a prevalent HIV-1 strain in China, characterized by predominantly single CCR5 tropism. This study found evidence that CRF07_BC has the ability to evolve into CXCR4 strains.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Medicine, Research & Experimental
Michael R. Ruff, Saadet Inan, Xiang Qun Shi, Joseph J. Meissler, Martin W. Adler, Toby K. Eisenstein, Ji Zhang
Summary: RAP-103, when co-administered with morphine, reduces the dose of morphine required for pain relief and the associated side effects. It also shows effectiveness as a non-opioid treatment for diabetic neuropathic pain.
Article
Immunology
Varsha M. Prabhu, Varsha Padwal, Shilpa Velhal, Sukeshani Salwe, Vidya Nagar, Priya Patil, Atmaram H. Bandivdekar, Vainav Patel
Summary: Vaginal transmission is the main route of HIV infection worldwide, with viral sequestration in vaginal epithelial cells leading to productive infection in co-cultivated PBMCs. The efficiency of trans-infection decreases over time, correlated with viral retention kinetics. This study reveals a previously unexplored role for the vaginal epithelium as a transient viral reservoir enabling infection of susceptible cell types, including specific CD4+ T lymphocyte subsets.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Virology
Massimiliano Secchi, Luca Vangelista
Summary: The fusion of potent CCR5 antagonist CCL5 5p12 5m with gp41-targeted fusion inhibitor C37 resulted in a protein design with potential therapeutic effects against HIV-1 infection.
Article
Multidisciplinary Sciences
Rodrigo R. R. Duarte, Oliver Pain, Robert L. Furler, Douglas F. Nixon, Timothy R. Powell
Summary: This study revealed the host genetic factors associated with protection against HIV-1, identifying 25 genetic loci and 15 susceptibility genes related to HIV-1 acquisition. Further functional studies and larger genetic research have the potential to enhance understanding of the host mechanisms related to protection against HIV-1.
Article
Medicine, Research & Experimental
Matthew Weichseldorfer, Yutaka Tagaya, Marvin Reitz, Anthony L. DeVico, Olga S. Latinovic
Summary: This study aims to understand the different conformations of CCR5 involved in HIV entry and identify the specific CCR5 populations that are best targeted to inhibit HIV-1 entry. Through quantification and visualization, it was found that a decreased surface presence of certain CCR5 subpopulations after infection represents a highly relevant target for future antiviral therapy strategies. The findings will contribute to the development of inhibitors to block CCR5 usage by HIV-1 and inform future HIV-1 vaccine design.
JOURNAL OF TRANSLATIONAL MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Xinming Li, Donglei Shi, Yihe Song, Yixiang Xu, Ying Gao, Wenjing Qiu, Xin Chen, Xiaokang Li, Yunyuan Huang, Yanjun Feng, Baoli Li, Yuan Guo, Jian Li
Summary: This study successfully developed two fluorescent turn-on probes (KXS-M1 and KXS-M2) for the highly selective and sensitive detection of monoamine oxidase A (MAO-A). Among them, KXS-M2 exhibited better fluorescence increment and sensitivity, and can be used for the diagnosis and treatment of heart failure.
CHINESE CHEMICAL LETTERS
(2022)
Article
Chemistry, Medicinal
Yunyuan Huang, Jiqun Wang, Jiaqi Liu, Donglei Shi, Xiaokang Li, Manjiong Wang, Taotao Lu, Bei Jiang, Conglong Xia, Houwen Lin, Yixiang Xu, Jian Li
Summary: This study developed a novel and rapid computer-guided combination drug-network-screening approach, which discovered a significant synergistic cardioprotective effect of the menthol-allethrin combination in vitro, providing a new synergistic mechanism and prospective agent for the treatment of heart failure.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Pharmacology & Pharmacy
Zhifan Mao, Wenwen Liu, Yunyuan Huang, Tianyue Sun, Keting Bao, Jiali Feng, Alexey Moskalev, Zelan Hu, Jian Li
Summary: This study investigates the anti-aging effects of sulfonylurea drugs, specifically chlorpropamide, on various organisms. The findings suggest that chlorpropamide delays aging and reduces doxorubicin-induced senescence by interacting with mitochondrial ATP-sensitive K+ channels and mitochondrial complex II. The study also reveals that chlorpropamide increases mitochondrial reactive oxygen species levels, which are associated with longevity signals.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Medicinal
Xiaokang Li, Jinwen Li, Yunyuan Huang, Qi Gong, Yan Fu, Yixiang Xu, Junyang Huang, Haolan You, Dong Zhang, Dan Zhang, Fei Mao, Jin Zhu, Huan Wang, Haiyan Zhang, Jian Li
Summary: This study proposed a novel therapeutic strategy by merging the key pharmacophores of an antidepressant and an anti-AD drug to develop multi-target-directed ligands for the comorbidity of AD and depression. Compound 5 showed promising triple-target bioactivities and alleviated depressive symptoms and cognitive dysfunction in mouse models.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Manjiong Wang, Tongke Tang, Ruoxi Li, Zhenghui Huang, Dazheng Ling, Lulu Zheng, Yan Ding, Taiping Liu, Wenyue Xu, Feng Zhu, Hui Min, Rachasak Boonhok, Fei Mao, Jin Zhu, Xiaokang Li, Lubin Jiang, Jian Li
Summary: This study designed and synthesized 35 novel derivatives based on quisinostat, with JX35 showing significant antimalarial effects in both in vitro and in vivo studies. JX35 exhibited potent inhibition against various parasite strains, suggesting its potential for simultaneous treatment, chemoprevention, and blocking malaria transmission. Mechanistic studies indicated that JX35 targets Pf HDAC1, showing stronger triple-stage antimalarial effects and lower toxicity compared to quisinostat.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yunyuan Huang, Haiyan Xu, Pei Wang, Rurong Gu, Xiaokang Li, Yixiang Xu, Jiqun Wang, Sicong Qiao, Donglei Shi, Zhaobing Gao, Jian Li
Summary: Combinatorial drug therapy is an emerging strategy for the treatment of diseases with complex pathological mechanisms. In this study, a computational screening approach was used to identify novel combination drugs for the treatment of epilepsy. The combination of guaifenesin-andrographolide was found to have synergistic anticonvulsant activities and alleviate the pathogenesis of epilepsy by affecting NMDA receptors.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Chemistry, Medicinal
Chao Zhang, Lan Wang, Yixiang Xu, Yunyuan Huang, Junyang Huang, Jin Zhu, Wei Wang, Wangsheng Li, Annan Sun, Xiaokang Li, Haiyan Zhang, Jian Li
Summary: Depression is a common psychiatric symptom in Alzheimer's disease, and its comorbidity increases the burden of treatment and care in elderly patients. Researchers proposed dual RAGE/SERT inhibitors as a potential treatment option for AD with comorbid depression and synthesized 34 ligands for evaluation. Compound 12 showed promising dual-target bioactivities and potential as a prototype for the treatment of AD with comorbid depression.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Taotao Lu, Xinyu Zheng, Fei Mao, Qiao Cao, Qin Cao, Jin Zhu, Xiaokang Li, Lefu Lan, Baoli Li, Jian Li
Summary: This study screened a library of drugs and found that the anthelmintic drug niclosamide (NIC) could enhance the efficacy of polymyxin B (PB) against multidrug-resistant Pseudomonas aeruginosa. Novel NIC-derived adjuvants were designed and synthesized, and one of them (adjuvant 15) exhibited synergistic activity with PB, effectively eliminating P. aeruginosa DK2 and slowing down the development of PB resistance.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Wang Li, Zhaolin Yun, Changjin Ji, Jie Tu, Wanzhen Yang, Jian Li, Na Liu, Chunquan Sheng
Summary: This study successfully improved the antifungal activity of novel sertraline derivatives, with compound D16 showing promising potential as a treatment for cryptococcal meningitis.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Keting Bao, Wenwen Liu, Zhouzhi Song, Jiali Feng, Zhifan Mao, Lingyuan Bao, Tianyue Sun, Zelan Hu, Jian Li, Jan Gruber
Summary: This study discovered a new small molecule derived from crotamiton, named JM03, which exhibits antioxidant, anti-hypertonic, and anti-aging effects. JM03 extends the lifespan of C. elegans by modulating the OSM-9 and SKN-1 signaling pathways.
Article
Pharmacology & Pharmacy
Jinlian Wei, Xin Chen, Yongyun Li, Ruoxi Li, Keting Bao, Liang Liao, Yuqing Xie, Tiannuo Yang, Jin Zhu, Fei Mao, Shuaishuai Ni, Renbing Jia, Xiaofang Xu, Jian Li
Summary: In this study, a novel anti-conjunctival melanoma mechanism of cucurbitacin B (CuB) was discovered. CuB inhibited CM cell proliferation and induced G2/M cell cycle arrest. CuB targeted GRP78 and FOXM1-KIF20A pathway, providing a potential therapeutic strategy for CM.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Pharmacology & Pharmacy
Yixiang Xu, Chao Zhang, Kai Jiang, Xinchun Yang, Feng Chen, Zhiyang Cheng, Jinlong Zhao, Jiaxing Cheng, Xiaokang Li, Xin Chen, Luoyifan Zhou, Hao Duan, Yunyuan Huang, Yaozu Xiang, Jian Li
Summary: To address the issue of separating ant-heart failure (HF) activity from glucose-lowering side-effects, the researchers conducted structural repurposing of the SGLT2 inhibitor EMPA. The optimized derivative JX01 showed weaker SGLT2-inhibitory activity and lower glucose-lowering side-effects, but better NHE1-inhibitory activity and HF mice cardioprotective effect. Furthermore, JX01 demonstrated good safety profiles and pharmacokinetic properties. This study provides a paradigm for discovering novel anti-HF drugs and indirectly highlights the importance of SGLT2-independent molecular mechanisms in the cardioprotective effects of SGLT2 inhibitors.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Chemistry, Medicinal
Jinlian Wei, Yongyun Li, Ruoxi Li, Xin Chen, Tiannuo Yang, Liang Liao, Yuqing Xie, Jin Zhu, Fei Mao, Renbing Jia, Xiaofang Xu, Jian Li
Summary: Propafenone, an FDA-approved antiarrhythmic medication, has been found to effectively inhibit the viability and homologous recombination pathway of conjunctival melanoma (CM) cells. The derivative D34, with promising structure-activity relationships, strongly suppressed CM cell proliferation, viability, and migration. Mechanistically, D34 increased gamma-H2AX nuclear foci and DNA damage by inhibiting the homologous recombination pathway, especially the MRE11-RAD50-NBS1 complex. Moreover, D34 dihydrochloride significantly suppressed tumor growth in a CM xenograft model without toxicity. This discovery suggests that propafenone derivatives targeting the MRE11-RAD50-NBS1 complex may provide a potential approach for CM therapy and enhance chemo- and radio-sensitivity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Donglei Shi, Wenwen Liu, Ying Gao, Xinming Li, Yunyuan Huang, Xiaokang Li, Tony D. James, Yuan Guo, Jian Li
Summary: This study presents a strategy to monitor and selectively eliminate senescent cells in mice during aging through controllable photodynamic therapy, which inhibited the age-related functional decline.
Letter
Biochemistry & Molecular Biology
Shuaishuai Ni, Qian Liu, Xin Chen, Lele Ding, Lili Cai, Fei Mao, Donglei Shi, Robert M. Hoffman, Jian Li, Lijun Jia
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2022)
