Design of HIV-1 Protease Inhibitors Active on Multidrug-Resistant Virus

2005 ◽  
Vol 48 (6) ◽  
pp. 1965-1973 ◽  
Author(s):  
Dominique L. N. G. Surleraux ◽  
Herman A. de Kock ◽  
Wim G. Verschueren ◽  
Geert M. E. Pille ◽  
Louis J. R. Maes ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Resistant Virus ◽  
Hiv 1

scholarly journals Primary HIV drug resistance among newly HIV type-1 diagnosed patients in St. Petersburg

2021 ◽  
Vol 13 (1) ◽  
pp. 70-79
Author(s):  
Thierry Ingabire ◽  
A. V. Semenov ◽  
E. V. Esaulenko ◽  
E. B. Zueva ◽  
A. N. Schemelev ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Direct Sequencing ◽  
Population Level ◽  
Multidrug Resistant ◽  
Antiretroviral Drugs ◽  
Drug Resistant ◽  
Resistant Virus ◽  
Primary Drug Resistance ◽  
Hiv 1

There is concern that the widespread use of antiretroviral drugs (ARV) to treat human immunodeficiency virus 1 (HIV-1) infection may result in the emergence of transmission of drug-resistant virus among persons newly infected with HIV-1. Russia is one of a growing number of countries in the world where drug-resistant HIV is becoming a serious health problem because it has the potential to compromise the efficacy of antiretroviral therapy (ART) at the population level.Materials and methods. We performed a genetic analysis of the HIV-1 plasma derived pol gene among the newly diagnosed ART-naïve HIV-1 infected patients during the period from November 2018 to October 2019 in the St. Petersburg Clinical Infectious Diseases Hospital named after S.P. Botkin. We used reverse transcriptase polymerase chain reaction (RT-PCR) followed by direct sequencing of PCR products to determine the prevalence of primary drug resistance (PDR) conferring mutations. HIV-1 genotypes were determined by phylogenetic analysis.Results. The predominant HIV-1 subtype was A1 (87.2%), followed by B (11.8%) and CRF06_cpx (1%). The overall prevalence of PDR was 11%. Virus with known resistance-conferring mutations to any nucleoside reverse transcriptase inhibitors (NRTIs) was found in 8 individuals, to any non NRTIs in 5 subjects, and to any protease inhibitors in 1 case. Multidrug-resistant virus was identified in 2 individuals (2%).Conclusion. The distribution of HIV-1 genotypes in St. Petersburg, Russia is diverse. The emerging prevalence of PDR in ART-naïve patients demonstrates the significance of constant monitoring due to the challenges it presents towards treatment.

scholarly journals Front Cover: Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants (ChemMedChem 8/2018)

ChemMedChem ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. 762-762
Author(s):  
Arun K. Ghosh ◽  
Kalapala Venkateswara Rao ◽  
Prasanth R. Nyalapatla ◽  
Satish Kovela ◽  
Margherita Brindisi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Front Cover ◽  
Cover Design ◽  
Hiv 1

scholarly journals Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

2004 ◽  
Vol 78 (6) ◽  
pp. 3123-3132 ◽  
Author(s):  
Bradley C. Logsdon ◽  
John F. Vickrey ◽  
Philip Martin ◽  
Gheorghe Proteasa ◽  
Jay I. Koepke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Surface Plasmon Resonance ◽  
Protease Inhibitors ◽  
Surface Plasmon ◽  
Active Site ◽  
Multidrug Resistant ◽  
Immunodeficiency Virus ◽  
Active Site Cavity ◽  
Hiv 1

ABSTRACT The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (Å) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease “flaps” stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 Å. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1′, S3, and S3′ pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k off rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k on and k off data (Kd = k off/k on) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms.

scholarly journals Extreme Multidrug Resistant HIV-1 Protease with 20 Mutations Is Resistant to Novel Protease Inhibitors with P1′-Pyrrolidinone or P2-Tris-tetrahydrofuran

2013 ◽  
Vol 56 (10) ◽  
pp. 4017-4027 ◽  
Author(s):  
Johnson Agniswamy ◽  
Chen-Hsiang Shen ◽  
Yuan-Fang Wang ◽  
Arun K. Ghosh ◽  
Kalapala Venkateswara Rao ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Hiv 1

scholarly journals Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Masayuki Amano ◽  
Pedro Miguel Salcedo-Gómez ◽  
Ravikiran S. Yedidi ◽  
Rui Zhao ◽  
Hironori Hayashi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Strong Hydrogen Bond ◽  
Term Therapy ◽  
Wild Type ◽  
Hiv 1 ◽  
Cns Targeting

ABSTRACT There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to ∼0.003 μM), with minimal cytotoxicity. These CNS-targeting PIs efficiently suppressed the replication of HIV-1 variants (EC50, 0.002 to ∼0.047 μM) that had been selected to propagate at high concentrations of conventional HIV-1 PIs. Such CNS-targeting PIs maintained their antiviral activity against HIV-2ROD as well as multidrug-resistant clinical HIV-1 variants isolated from AIDS patients who no longer responded to existing antiviral regimens after long-term therapy. Long-term drug selection experiments revealed that the emergence of resistant-HIV-1 against these CNS-targeting PIs was substantially delayed. In addition, the CNS-targeting PIs showed the most favorable CNS penetration properties among the tested compounds, including various FDA-approved anti-HIV-1 drugs, as assessed with the in vitro blood-brain barrier reconstruction system. Crystallographic analysis demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting PIs form strong hydrogen-bond interactions with HIV-1 protease (PR) active site. Moreover, both the P1-3,5-bis-fluorophenyl and P1-para-monofluorophenyl rings sustain greater van der Waals contacts with PR than in the case of darunavir (DRV). The data suggest that the present CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 strains and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications.

scholarly journals Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants

2017 ◽  
Vol 60 (10) ◽  
pp. 4267-4278 ◽  
Author(s):  
Arun K. Ghosh ◽  
Kalapala Venkateswara Rao ◽  
Prasanth R. Nyalapatla ◽  
Heather L. Osswald ◽  
Cuthbert D. Martyr ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Design And Development ◽  
Hiv 1

Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains

2003 ◽  
Vol 46 (9) ◽  
pp. 1764-1768 ◽  
Author(s):  
Hirokazu Tamamura ◽  
Yasuhiro Koh ◽  
Satoshi Ueda ◽  
Yoshikazu Sasaki ◽  
Tomonori Yamasaki ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv 1
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