HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues
In this study, we explored analogs of darunavir with a P1 phosphonate modification in combination with increasing size of the P1' hydrophobic group and various P2' moieties to improve potency against resistant variants. The phosphonate moiety substantially improved potency against highly mutated and resistant HIV-1 protease variants, but only when combined with more hydrophobic moieties at the P1' and P2' positions. Phosphonate analogs with a larger hydrophobic P1' moiety maintained excellent antiviral potency against a panel of highly resistant HIV-1 variants, with significantly improved resistance profiles. The cocrystal...
Source: European Journal of Medicinal Chemistry - May 27, 2023 Category: Chemistry Authors: Gordon J Lockbaum Linah N Rusere Mina Henes Klajdi Kosovrasti Desaboini Nageswara Rao Ean Spielvogel Sook-Kyung Lee Ellen A Nalivaika Ronald Swanstrom Nese Kurt Yilmaz Celia A Schiffer Akbar Ali Source Type: research
HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues
In this study, we explored analogs of darunavir with a P1 phosphonate modification in combination with increasing size of the P1' hydrophobic group and various P2' moieties to improve potency against resistant variants. The phosphonate moiety substantially improved potency against highly mutated and resistant HIV-1 protease variants, but only when combined with more hydrophobic moieties at the P1' and P2' positions. Phosphonate analogs with a larger hydrophobic P1' moiety maintained excellent antiviral potency against a panel of highly resistant HIV-1 variants, with significantly improved resistance profiles. The cocrystal...
Source: European Journal of Medicinal Chemistry - May 27, 2023 Category: Chemistry Authors: Gordon J Lockbaum Linah N Rusere Mina Henes Klajdi Kosovrasti Desaboini Nageswara Rao Ean Spielvogel Sook-Kyung Lee Ellen A Nalivaika Ronald Swanstrom Nese Kurt Yilmaz Celia A Schiffer Akbar Ali Source Type: research
HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues
In this study, we explored analogs of darunavir with a P1 phosphonate modification in combination with increasing size of the P1' hydrophobic group and various P2' moieties to improve potency against resistant variants. The phosphonate moiety substantially improved potency against highly mutated and resistant HIV-1 protease variants, but only when combined with more hydrophobic moieties at the P1' and P2' positions. Phosphonate analogs with a larger hydrophobic P1' moiety maintained excellent antiviral potency against a panel of highly resistant HIV-1 variants, with significantly improved resistance profiles. The cocrystal...
Source: European Journal of Medicinal Chemistry - May 27, 2023 Category: Chemistry Authors: Gordon J Lockbaum Linah N Rusere Mina Henes Klajdi Kosovrasti Desaboini Nageswara Rao Ean Spielvogel Sook-Kyung Lee Ellen A Nalivaika Ronald Swanstrom Nese Kurt Yilmaz Celia A Schiffer Akbar Ali Source Type: research
Viruses, Vol. 15, Pages 1123: Efficacy and Durability of Dolutegravir- or Darunavir-Based Regimens in ART-Na & iuml;ve AIDS- or Late-Presenting HIV-Infected Patients
Conclusions: Dolutegravir and darunavir showed similar efficacy in AIDS- and late-presenting patients. A higher risk of TD due to CNS toxicity was observed with dolutegravir, and a higher probability of treatment simplification with darunavir. (Source: Viruses)
Source: Viruses - May 8, 2023 Category: Virology Authors: Massimiliano Fabbiani Melissa Masini Barbara Rossetti Arturo Ciccullo Vanni Borghi Filippo Lagi Amedeo Capetti Manuela Colafigli Francesca Panza Gianmaria Baldin Cristina Mussini Gaetana Sterrantino Damiano Farinacci Francesca Montagnani Mario Tumbarello Tags: Article Source Type: research
Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation
Eur J Med Chem. 2023 Apr 21;255:115385. doi: 10.1016/j.ejmech.2023.115385. Online ahead of print.ABSTRACTStructure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 protease inhibitors are described. These inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone...
Source: European Journal of Medicinal Chemistry - May 7, 2023 Category: Chemistry Authors: Arun K Ghosh Jennifer L Mishevich Satish Kovela Ryan Shaktah Ajay K Ghosh Megan Johnson Yuan-Fang Wang Andres Wong-Sam Johnson Agniswamy Masayuki Amano Yuki Takamatsu Shin-Ichiro Hattori Irene T Weber Hiroaki Mitsuya Source Type: research
Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation
Eur J Med Chem. 2023 Apr 21;255:115385. doi: 10.1016/j.ejmech.2023.115385. Online ahead of print.ABSTRACTStructure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 protease inhibitors are described. These inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone...
Source: European Journal of Medicinal Chemistry - May 7, 2023 Category: Chemistry Authors: Arun K Ghosh Jennifer L Mishevich Satish Kovela Ryan Shaktah Ajay K Ghosh Megan Johnson Yuan-Fang Wang Andres Wong-Sam Johnson Agniswamy Masayuki Amano Yuki Takamatsu Shin-Ichiro Hattori Irene T Weber Hiroaki Mitsuya Source Type: research
Viruses, Vol. 15, Pages 762: Efficacy of Dolutegravir versus Darunavir in Antiretroviral First-Line Regimens According to Resistance Mutations and Viral Subtype
Conclusions: In line with randomized trials, DTG-based first-line regimens showed an overall superior efficacy compared with DRV-based regimens. GRT may still play a role in identifying patients more at risk of VF and in guiding the choice of an antiretroviral backbone. (Source: Viruses)
Source: Viruses - March 16, 2023 Category: Virology Authors: Pierluigi Francesco Salvo Damiano Farinacci Arturo Ciccullo Vanni Borghi Stefano Rusconi Annalisa Saracino William Gennari Bianca Bruzzone Ilaria Vicenti Annapaola Callegaro Antonio Di Biagio Maurizio Zazzi Simona Di Giambenedetto Alberto Borghetti Tags: Article Source Type: research
Viruses, Vol. 15, Pages 720: Causes of HIV Treatment Interruption during the Last 20 Years: A Multi-Cohort Real-Life Study
In conclusion, our data on more than 4400 PWH show that adverse events have represented the most frequent cause of treatment interruptions in the first year of ART (3.84%). Treatment discontinuations were more frequent during the first year of follow-up and decreased thereafter. First-generation PI in both naïve and experienced PWH, and EVG/c, in experienced PWH, were associated with a higher risk of treatment interruptions. (Source: Viruses)
Source: Viruses - March 10, 2023 Category: Virology Authors: Andrea De Vito Elena Ricci Barbara Menzaghi Giancarlo Orofino Canio Vito Martinelli Nicola Squillace Lucia Taramasso Giuseppe Vittorio De Socio Chiara Molteni Laura Valsecchi Cecilia Costa Benedetto Maurizio Celesia Giustino Parruti Giovanni Francesco Pel Tags: Article Source Type: research
Promising Repurposed Antiviral Molecules to Combat SARS-CoV-2: A Review
Curr Pharm Biotechnol. 2023 Mar 2. doi: 10.2174/1389201024666230302113110. Online ahead of print.ABSTRACTCOVID-19, an extremely transmissible and pathogenic viral disease, triggered a global pandemic that claimed lives worldwide. To date, there is no clear and fully effective treatment for COVID-19 disease. Nevertheless, the urgency to discover treatments that can turn the tide has led to the development of a variety of preclinical drugs that are potential candidates for probative results. Although most of these supplementary drugs are constantly being tested in clinical trials against COVID-19, recognized organizations ha...
Source: Current Pharmaceutical Biotechnology - March 2, 2023 Category: Biotechnology Authors: Yashumati Ratan Aishwarya Rajput Vivek Jain Dinesh Kumar Mishra Rupesh K Gautam Ashutosh Pareek Source Type: research
Promising Repurposed Antiviral Molecules to Combat SARS-CoV-2: A Review
Curr Pharm Biotechnol. 2023 Mar 2. doi: 10.2174/1389201024666230302113110. Online ahead of print.ABSTRACTCOVID-19, an extremely transmissible and pathogenic viral disease, triggered a global pandemic that claimed lives worldwide. To date, there is no clear and fully effective treatment for COVID-19 disease. Nevertheless, the urgency to discover treatments that can turn the tide has led to the development of a variety of preclinical drugs that are potential candidates for probative results. Although most of these supplementary drugs are constantly being tested in clinical trials against COVID-19, recognized organizations ha...
Source: Current Pharmaceutical Biotechnology - March 2, 2023 Category: Biotechnology Authors: Yashumati Ratan Aishwarya Rajput Vivek Jain Dinesh Kumar Mishra Rupesh K Gautam Ashutosh Pareek Source Type: research
