Article
Multidisciplinary Sciences
Qiankun Wang, Hongbo Gao, Kolin M. Clark, Christian Shema Mugisha, Keanu Davis, Jack P. Tang, Gray H. Harlan, Carl J. DeSelm, Rachel M. Presti, Sebla B. Kutluay, Liang Shan
Summary: HIV-1's rapid evolution and high mutation rates enable it to evade the host immune system, but intervention targeting the protease activity with the inflammasome sensor CARD8 has shown promise in clearing latent HIV-1 infection.
Article
Biochemistry & Molecular Biology
Roberto Arrigoni, Luigi Santacroce, Andrea Ballini, Luigi Leonardo Palese
Summary: The availability of drugs capable of blocking microorganism replication is a major accomplishment in medicine, but the increasing number of resistant strains poses a significant challenge for infectious disease treatment. Therefore, the search for new potential ligands for pathogens' life cycle is a crucial research area today.
Review
Pharmacology & Pharmacy
Matthew Weichseldorfer, Marvin Reitz, Olga S. Latinovic
Summary: Combined antiretroviral therapy (cART) is widely recommended for controlling HIV-1 replication and improving the quality of life of infected individuals. However, latent infected cells remain a major barrier to treatment efficacy in the long term.
Article
Multidisciplinary Sciences
Shanshan Wu, Huiyu Li, Ao Ma
Summary: The primary goal of protein science is to understand the functional mechanisms of proteins and their transitions between different functional structures. However, identifying the exact reaction coordinates in complex molecules remains challenging. In this study, the researchers used a generalized work functional to discover the exact reaction coordinates for the flap opening of HIV-1 protease, providing a precise definition of collectivity and cooperativity in protein dynamics.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Kolin M. Clark, Josh G. Kim, Qiankun Wang, Hongbo Gao, Rachel M. Presti, Liang Shan
Summary: The sensitization of the CARD8 inflammasome to non-nucleoside reverse transcriptase inhibitors (NNRTIs) can be achieved through chemical inhibition of the negative regulator DPP9. The DPP9 inhibitor Val-boroPro (VbP) can kill HIV-1-infected cells without NNRTIs and synergize with NNRTIs to promote clearance of infected cells. This offers a promising strategy for enhancing NNRTI efficacy in eliminating HIV-1 reservoirs.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Simeon Eche, Ajit Kumar, Nelson Sonela, Michelle L. Gordon
Summary: The study found that HIV-1 PR variants with multidrug resistance mutations exhibited increased relative resistance to LPV and DRV, along with a progressive decrease in catalytic efficiency. The structural changes in the mutant HIV-1 PR were attributed to intrinsic alterations caused by multidrug resistance mutations affecting the binding landscape of LPV and DRV. Despite DRV showing superiority over LPV in inhibiting the HIV-1 PR variants, the structural changes resulting from mutations selected during LPV therapy could shape the outcome of DRV treatment after the therapy switch.
Article
Virology
Caroline O. Tabler, Sarah J. Wegman, Jiji Chen, Hari Shroff, Najwa Alhusaini, John C. Tilton
Summary: HIV-1 protease is activated within producer cells prior to the release of free virions, and the acceleration of protease activation kinetics can lead to efficient elimination of HIV-infected cells. This finding helps resolve the long-standing question of when protease is activated during viral assembly and suggests a potential strategy for eradicating the viral reservoirs.
JOURNAL OF VIROLOGY
(2022)
Article
Biophysics
Minghan Li, Wei Li, Yicen Xiao, Qianshan Liu, Liyuan Liang, Deqiang Wang, Wenli Huang, Liang Wang
Summary: Inhibition of HIV-1 protease activity can be achieved by exposure to Co-60 gamma-radiation, leading to substantial loss of proteolytic efficiency towards GagPol polypeptide. The effectiveness of gamma-radiation in inactivating viral protein function is demonstrated, which may serve as a complementary approach to the design of HIV-1 PR inhibitors.
BIOSENSORS & BIOELECTRONICS
(2021)
Article
Biochemistry & Molecular Biology
Veronna Marie, Michelle Gordon
Summary: This study used molecular dynamics simulations to explore the co-evolutionary molecular mechanisms of resistance in HIV-1 PR and Gag, showing that resistance mutations in PR can alter drug binding and exacerbate binding when mutant PRs are bound to mutated Gag cleavage sites. The research also demonstrated that co-selection of mutations in both enzyme and substrate can lead to complex mechanisms of resistance, affecting the active site and flap flexibility in PR.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Multidisciplinary Sciences
Jerry Joe E. K. Harrison, Dario Oliveira Passos, Jessica F. Bruhn, Joseph D. Bauman, Lynda Tuberty, Jeffrey J. DeStefano, Francesc Xavier Ruiz, Dmitry Lyumkis, Eddy Arnold
Summary: In this study, the cryo-electron microscopy structure of stable HIV-1 Pol was determined, revealing that RT in the Pol has a similar arrangement to the mature RT heterodimer. The dimerization of RT may activate proteolytic processing by bringing two PR monomers together. This finding suggests that HIV-1 leverages the dimerization interfaces in Pol to regulate assembly and maturation of polyprotein precursors.
Article
Biochemistry & Molecular Biology
Sunday N. Okafor, Abigail Meyer, Jay Gadsden, Fadi Ahmed, Lilian Guzman, Hashim Ahmed, Jose A. Fernandez Romero, Pavimol Angsantikul
Summary: This study screened FDA-approved and investigational drugs for their potential as HIV-1 protease inhibitors. The findings revealed that CBR003PS and CBR013PS exhibited significant binding affinity to the HIV-1 protease with high stability, showing potential for repurposing as HIV-1 protease inhibitors.
Article
Multidisciplinary Sciences
Manabu Aoki, Hiromi Aoki-Ogata, Haydar Bulut, Hironori Hayashi, Nobutoki Takamune, Naoki Kishimoto, Hiroki Tanaka, Nobuyo Higashi-Kuwata, Shin-ichiro Hattori, Debananda Das, Kalapala Venkateswara Rao, Kazuya Iwama, David A. Davis, Kazuya Hasegawa, Kazutaka Murayama, Robert Yarchoan, Arun K. Ghosh, Alice K. Pau, Shinichi Machida, Shogo Misumi, Hiroaki Mitsuya
Summary: This study found that a multidrug-resistant HIV-1 variant HIVKGD is highly susceptible to a HIV-1 protease inhibitor GRL-142, which disrupts the nuclear import of the virus. The highly INSTI-resistant HIV-1 variants were also sensitive to GRL-142, indicating that NLS-targeting agents may serve as salvage therapy for INSTI-resistant individuals.
Article
Biology
Ean Spielvogel, Sook-Kyung Lee, Shuntai Zhou, Gordon J. Lockbaum, Mina Henes, Amy Sondgeroth, Klajdi Kosovrasti, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer, Ronald Swanstrom
Summary: Darunavir is a potent HIV-1 protease inhibitor that achieves high drug concentrations in vivo. Little is known about its resistance pathway. In this study, resistance to high drug concentrations of 10 PIs and their structural precursor DRV were selected. Two resistance pathways (anchored by protease mutations I50V or I84V) were identified, influenced by changes in the inhibitor's P1' and P2' positions. Viral variants from these pathways also showed different selection of compensatory mutations in Gag cleavage sites.
Article
Biochemistry & Molecular Biology
Bowen Pan, Sumei Li, Junwei Xiao, Xin Yang, Shouxia Xie, Ying Zhou, Jian Yang, Ying Wei
Summary: This study screened potential antiviral compounds from Sarcandra glabra and investigated their inhibitory effects on HIV-1 and Cathepsin L proteases. The results showed that the extracts from Sarcandra glabra inhibited both proteases, with chlorogenic acid identified as the most potent inhibitor. These findings suggest that Sarcandra glabra extracts and its active ingredients may have dual-inhibition functions against viral proteases and could be used for preventing or treating viral infections, including SARS-CoV-2.
Article
Materials Science, Multidisciplinary
Anuj Bisht, Michael Kalina, Eylul Suadiye, Gunther Richter, Eugen Rabkin
Summary: In this study, nanoscale bimetallic strips were fabricated by one-sided coating with Pd, leading to slight bending of the strips. The temperature-induced shape changes of the Au-Pd strips were investigated via in-situ thermal actuation. The results demonstrate that single crystalline metallic nanowhiskers with controlled curvature, chemical composition, and thermal behavior can be produced using interface engineering and chemical interdiffusion.
Article
Chemistry, Medicinal
Juliana Castro-Amorim, Ana Oliveira, Ashis K. Mukherjee, Maria J. Ramos, Pedro A. Fernandes
Summary: In this study, the catalytic mechanism of RVV-X was determined using a density functional theory/molecular mechanics approach. The results showed that the catalytic process occurs in two steps, involving nucleophilic attack and protonation of the substrate. Zn2+ was found to play a unique role in catalysis by lowering the pKa of the Zn2+-bound water molecule.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Joao Carneiro, Rita P. Magalhaes, Victor de la Oliva M. Roque, Manuel Simoes, Diogo Pratas, Sergio F. Sousa
Summary: This study developed a machine learning multitechnique consensus workflow to predict the protein targets of molecules with confirmed inhibitory activity against biofilm formation by Pseudomonas aeruginosa. The implemented algorithm is freely available and can be improved as more data become available.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2023)
Article
Chemistry, Medicinal
Juliana Castro-Amorim, Ana Novo de Oliveira, Saulo Luis Da Silva, Andreimar M. Soares, Ashis K. Mukherjee, Maria Joao Ramos, Pedro A. . Fernandes
Summary: Snake venom-secreted phospholipase A(2) (svPLA(2)) enzymes play a crucial role in envenoming by disrupting the cell membrane's integrity and inducing various pharmacological effects. However, the reaction mechanisms of svPLA(2) are still not fully understood. This review presents and analyzes the most plausible reaction mechanisms, including the single-water mechanism and the assisted-water mechanism. The importance of interfacial activation and a potential catalytic mechanism for noncatalytic PLA(2)-like proteins are also discussed.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Jovana B. Araskov, Natalia Maciejewska, Mateusz Olszewski, Aleksandar Visnjevac, Vladimir Blagojevic, Henrique S. Fernandes, Sergio F. Sousa, Adrian Puerta, Jose M. Padron, Berta Barta Hollo, Miguel Monge, Maria Rodriguez-Castillo, Jose M. Lopez-de-Luzuriaga, Ozlem Uguz, Atif Koca, Tamara R. Todorovic, Nenad R. Filipovic
Summary: In this study, three neutral Zn(II) complexes with pyridine-based TH ligands were synthesized and characterized. The influence of the ligands' charge on the structure, intermolecular interactions, and photophysical properties was investigated. The deprotonation of the ligands mainly affected the relative energies of electronic levels in the complexes, resulting in similar photoluminescence mechanisms and quantum yields. The substituents at the ligands' periphery had localized effects on the selected quantum molecular descriptors of the complexes.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Review
Biochemistry & Molecular Biology
Maria F. Araujo, Elisabete M. S. Castanheira, Sergio F. Sousa
Summary: Insecticides are crucial in controlling the spread of insect-borne diseases and protecting crop health. They are formulated to kill or manage insect populations, but their use can have potential consequences on non-target species, the environment, and human health. It is important to follow recommended instructions and employ integrated pest management practices for responsible and sustainable utilization. This review article provides a comprehensive examination of insecticides, including their modes of action, physiological targets, impacts on the environment and human health, and alternatives.
Article
Biochemistry & Molecular Biology
Joao P. M. De Sousa, Nuno C. S. A. Oliveira, Pedro A. Fernandes
Summary: (S)-Norcoclaurine is a crucial compound for the biosynthesis of benzylisoquinoline alkaloids, including various drugs. The genetic modification of (S)-norcoclaurine synthase has been proven to be an effective strategy for large-scale bioproduction of (S)-norcoclaurine in heterologous hosts such as bacteria or yeast.
Article
Chemistry, Physical
Rui P. P. Neves, Bruno Araujo, Maria J. Ramos, Pedro A. Fernandes
Summary: The bacterium Rhodococcus erythropolis (strain IGTS8) has a significant potential in the industry for its ability to remove sulfur from crude oil through the 4S metabolic pathway. The rate-limiting enzyme DszC is prone to feedback inhibition. Molecular docking and dynamics simulations were used to identify binding sites wherein two products of the pathway induce feedback inhibition. The study revealed four potential binding sites, and the proposed mechanism of feedback inhibition involves disturbance of oligomerization and weakening of key interactions within DszC.
Article
Pharmacology & Pharmacy
Carlos F. M. Silva, Teresa Leao, Filipa Dias, Ana M. Tomas, Diana C. G. A. Pinto, Eduardo F. T. Oliveira, Ana Oliveira, Pedro A. Fernandes, Artur M. S. Silva
Summary: Leishmaniasis is a neglected disease mainly affecting people in developing countries, with approximately 350 million people at risk. The lack of vaccines and chemotherapy has led to an increase in the incidence of the disease. A computational study focusing on a specific enzyme of the parasite has identified potential inhibitors, indicating the promise of using these compounds for developing novel antileishmanial drugs.
Article
Chemistry, Medicinal
Mariana Novo Belchor, Caroline Ramos da Cruz Costa, Airam Roggero, Laila L. F. Moraes, Ricardo Samelo, Isabelly Annunciato, Marcos Antonio de Oliveira, Sergio F. Sousa, Marcos Hikari Toyama
Summary: In this study, in silico tools were used to evaluate the potential of quercetin methylated derivatives in inhibiting snake venom toxins and phospholipase A2. The results showed that certain residues, including Leu2, Phe5, Tyr28, glycine in the calcium-binding loop, His48, and Asp49, were the main targets for inhibition. These findings are important for further research on the anti-inflammatory effects of quercetin derivatives.
Article
Chemistry, Medicinal
Joas T. S. Coimbra, Pedro A. Fernandes, Maria J. Ramos
Summary: Due to antibiotic resistance, it is crucial to explore new antibiotics and/or strategies to counter resistance. This study used molecular dynamics simulations and quantum mechanics/molecular mechanics methods to investigate the degradation of a streptogramin B antibiotic by Vgb lyase and assess the impact of point mutations on the reaction. The findings provide valuable insights into the linearization reactions of cyclic antibiotics and aid in the development of novel strategies against antibiotic resistance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Microbiology
E. Mauro, D. Lapaillerie, C. Tumiotto, C. Charlier, F. Martins, S. F. Sousa, M. Metifiot, P. Weigel, K. Yamatsugu, M. Kanai, H. Munier-Lehmann, C. Richetta, M. Maisch, J. Dutrieux, J. Batisse, M. Ruff, O. Delelis, P. Lesbats, V. Parissi
Summary: Researchers used AlphaLISA technology to monitor the interaction between retroviral intasomes and nucleosomes, and identified drugs that disrupt or prevent their association, inhibiting HIV-1 integration.
Article
Materials Science, Multidisciplinary
Fabio G. Martins, Chanchal Kiran Thakur, Chandrabose Karthikeyan, N. S. Hari Narayana Moorthy, Sergio F. Sousa
Summary: This study used computational models to investigate the pH dependent loading of doxorubicin onto multiwalled carbon nanotubes (MWCNTs). The results showed that systems under acidic conditions had lower adsorption compared to their neutral counterparts, and carbohydrate-modified lysinated MWCNTs had higher adsorption compared to pristine or carboxylated nanotubes. These findings are consistent with previous experimental work and suggest that sugar-tethered multiwalled carbon nanotubes hold promise for doxorubicin delivery to cancer cells.
Article
Chemistry, Multidisciplinary
How Chee Ong, Joao T. S. Coimbra, Maria J. Ramos, Bengang Xing, Pedro A. Fernandes, Felipe Garcia
Summary: Mitochondrial targeting is a promising strategy for treating various diseases, and Triphenylphosphonium (TPP+) moieties have been widely used for this purpose. However, the core structure of TPP+ remains largely unchanged, so this study explored the use of novel phosphorus-nitrogen based frameworks as mitochondrial delivery vectors. The phosphazenylphosphonium (PPN+) moiety was found to be highly effective in delivering cargo to mitochondria, with unique electronic properties and high lipophilicity.
Article
Chemistry, Multidisciplinary
Carola Jerves, Rui P. P. Neves, Saulo L. da Silva, Maria J. Ramos, Pedro A. Fernandes
Summary: The PETase enzyme from Ideonella sakaiensis can degrade PET at room temperature. Computational enzyme optimization can accelerate enzyme engineering. Mutations can stabilize transition states and decrease activation barriers. Rational enzyme engineering on PETase and other enzymes is encouraged.
NEW JOURNAL OF CHEMISTRY
(2023)
Article
Chemistry, Physical
Tatiana F. Vieira, Nuno M. F. S. A. Cerqueira, Manuel Simoes, Sergio F. Sousa
Summary: PqsD is an enzyme involved in the synthesis of essential secondary metabolites for Pseudomonas quinolone signal (PQS) inducer molecules. Inhibition of PqsD activity can inhibit biofilm formation and can be combined with PqsR inhibition. This study used computational methods to screen and select eight compounds as potential quorum sensing inhibitors.
MOLECULAR SYSTEMS DESIGN & ENGINEERING
(2024)