Bis‐Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance

Ghosh, Arun K.; Sridhar, P.; Kumaragurubaran, Nagaswamy; Koh, Yasuhiro; Weber, Irene T.; Mitsuya, Hiroaki

doi:10.1002/cmdc.200600103

Cited by 112 publications

(95 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In preliminary studies inhibitor 1 has shown extremely potent antiviral activity on HIV-1 9 . Inhibitor 1 showed about 10-fold higher potency for wild type strains of HIV than the chemically related darunavir.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, new antiviral inhibitors are being developed 8 . One successful approach is to design inhibitors that provide more interactions with the main chain atoms of PR 9 . These interactions cannot easily be changed by mutation.…”

Section: Introductionmentioning

confidence: 99%

“…These mutations had smaller structural changes in the interactions with darunavir, and little change in the inhibition relative to wild type PR. Figure 1) is a potent new antiviral inhibitor derived from darunavir in which the aniline group has been replaced by a 1, 3-benzodioxole group 9,17 . This chemical change is expected to alter the affinity of the compound, especially for mutants PR D30N and PR I50V because the aniline group of darunavir interacts with Asp30 and Ile50.…”

Section: Introductionmentioning

confidence: 99%

“…However, crystal structures show that many of the HIV PR interactions are similar for inhibitor 1 and darunavir 17 . The antiviral data show that inhibitor 1 is highly potent against HIV-infected cells with IC 50 values of 0.2-0.5 nM compared to 3 nM for darunavir, and has minimal cytotoxicity 9,17 . Here, the structures and in vitro inhibition data are reported for inhibitor 1 and PR variants with the single substitutions D30N, I50V, V82A and I84V.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease

et al. 2007

View full text Add to dashboard Cite

The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold and 3-fold, respectively, for PR D30N , PR I50V , PR V82A and PR I84V relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PR D30N , where inhibitor 1 was approximately threefold less potent. The high resolution (1.11-1.60 Å) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PR D30N and PR V82A showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PR I50V and PR I84V . Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease

et al. 2007

View full text Add to dashboard Cite

show abstract

“…We have designed and synthesized a series of nonpeptidyl protease inhibitors (PIs) that are potent against HIV-1 variants resistant to a number of PIs. One such anti-HIV-1 agent, darunavir (DRV), containing a structure-based designed privileged nonpeptidic P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl-urethane (bis-THF) (9,10,16), has been used worldwide as a first-line drug for the treatment of drug-naive patients with HIV-1 infection and those who harbor multidrug-resistant HIV-1 (HIV-1 MDR ) variants and do not respond to previously existing highly active antiretroviral therapy (HAART) regimens. It has been reported that DRV has a high genetic barrier to development of HIV-1 resistance (4,5) and that most patients with HIV-1 infection treated with other PIs respond favorably to DRV-based salvage therapy (19), while a variety of amino acid substitutions potentially related to HIV-1 resistance to DRV have been reported (4,19).…”

mentioning

confidence: 99%

In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

Koh

Amano

Towata

et al. 2010

J Virol

Self Cite

180

View full text Add to dashboard Cite

We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1MIX) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1MIX became highly resistant to DRV, with a 50% effective concentration (EC50) ∼333-fold greater than that against HIV-1NL4-3. HIV-1MIX at passage 51 (HIV-1MIXP51 ) replicated well in the presence of 5 μM DRV and contained 14 mutations. HIV-1MIXP51 was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1MIXP51 had a resemblance with HIV-1C of the HIV-1MIX population, and selection using HIV-1C was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1CP51 , likely contributed to conferring a replication advantage on HIV-1MIXP51 by reducing intravirion cyclophilin A content. HIV-1MIXP51 apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1MIX through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1MIXP51 should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.

show abstract

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Ghosh

Anderson

Mitsuya

2010

Burger's Medicinal Chemistry and Drug Discovery

Self Cite

View full text Add to dashboard Cite

Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.

show abstract

Bis‐Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance

Cited by 112 publications

References 93 publications

Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease

Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease

In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Contact Info

Product

Resources

About