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 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 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.

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 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

scholarly journals 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 ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. 803-815 ◽  
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 ◽  
Hiv 1

scholarly journals C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

2015 ◽  
Vol 90 (5) ◽  
pp. 2180-2194 ◽  
Author(s):  
Manabu Aoki ◽  
Hironori Hayashi ◽  
Ravikiran S. Yedidi ◽  
Cuthbert D. Martyr ◽  
Yuki Takamatsu ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Oxygen Atom ◽  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Carbonyl Oxygen ◽  
Carbonyl Oxygen Atom ◽  
Strong Hydrogen Bond ◽  
Wild Type ◽  
Genetic Barrier ◽  
Hiv 1

ABSTRACTWe identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 μM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRVRP51); the three compounds remained active against HIV-1DRVRP51with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR.IMPORTANCEDarunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIVDRVR) has recently been observedin vivoandin vitro. Here, we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano-tetrahydrofuran (Tp-THF) moiety with a C-5 hydroxyl (GRL-015, -085, and -097) which potently suppress the replication of HIVDRVR. Moreover, the emergence of HIV-1 strains resistant to the three compounds was considerably delayed compared to the case of DRV. The C-5 hydroxyl formed a strong hydrogen bonding interaction with the carbonyl oxygen atom of Gly48 of protease as examined in the structural analyses. Interestingly, a compound with Tp-THF lacking the hydroxyl moiety substantially decreased activity against HIVDRVR. The three novel compounds should be further developed as potential drugs for treating individuals harboring wild-type and multi-PI-resistant HIV variants as well as HIVDRVR.

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