scholarly journals Bile pigments as HIV-1 protease inhibitors and their effects on HIV-1 viral maturation and infectivity in vitro

1996 ◽  
Vol 320 (2) ◽  
pp. 681-686 ◽  
Author(s):  
Fiona McPHEE ◽  
Patricia S. CALDERA ◽  
Guy W. BEMIS ◽  
Antony F. McDONAGH ◽  
Irwin D. KUNTZ ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Cultured Cells ◽  
Dimethyl Ester ◽  
Molecular Shape ◽  
Viral Assembly ◽  
Bile Pigments ◽  
Viral Maturation ◽  
Viral Polyprotein ◽  
Hiv 1

Using recently developed molecular-shape description algorithms, we searched the Available Chemical Directory for known compounds similar in shape to the potent HIV-1 protease inhibitor Merck L-700,417; 15 compounds most similar in shape to the inhibitor were selected for testing in vitro. Four of these inhibited the protease at 100 µM or less and the most active of the four were the naturally occurring pigments biliverdin and bilirubin. Biliverdin and bilirubin inhibited recombinant HIV-1 protease in vitro at pH 7.8 with Ki values of approx. 1 µM, and also inhibited HIV-2 and simian immunodeficiency virus proteases. The related pyrrolic pigments stercobilin, urobilin, biliverdin dimethyl ester and xanthobilirubic acid showed similar inhibitory activity at low micromolar concentrations. Biliverdin, bilirubin and xanthobilirubic acid did not inhibit viral polyprotein processing in cultured cells, but they reduced viral infectivity significantly. At 100 µM, xanthobilirubic acid affected viral assembly, resulting in a 50% decrease in the generation of infectious particles. In contrast, at the same concentrations biliverdin and bilirubin exerted little or no effect on viral assembly but blocked infection of HeLaT4 cells by 50%. These results suggest that bile pigments might be a new class of potential lead compounds for developing protease inhibitors and they raise the question of whether hyperbilirubinaemia can influence the course of HIV infection.

scholarly journals Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against the Initial Autocleavage in Gag-Pol Polyprotein Processing

2012 ◽  
Vol 56 (7) ◽  
pp. 3620-3628 ◽  
Author(s):  
David A. Davis ◽  
Erin E. Soule ◽  
Katharine S. Davidoff ◽  
Sarah I. Daniels ◽  
Nicole E. Naiman ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Initial Step ◽  
Hiv Protease ◽  
Translation System ◽  
Hiv Therapy ◽  
Viral Maturation ◽  
Few Data ◽  
Hiv 1 ◽  
Mature Protease

ABSTRACTInhibitors of HIV protease have proven to be important drugs in combination anti-HIV therapy. These inhibitors were designed to target mature protease and prevent viral particle maturation by blocking Gag and Gag-Pol processing by mature protease. Currently there are few data assessing the ability of these protease inhibitors to block the initial step in autoproteolytic processing of Gag-Pol. This unique step involves the dimerization of two Gag-Pol polyproteins and autocleavage of the Gag-Pol polyprotein by the embedded dimeric protease. We developed a plasmid encoding a modified form of Gag-Pol that can undergo autoprocessing only at the initial cleavage site between p2 and nucleocapsid. Using anin vitrotranscription/translation system, we assessed the ability of six different approved protease inhibitors (darunavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir) to block this initial autocleavage step. Of these inhibitors, darunavir and saquinavir were the most effective. Darunavir and saquinavir were also the most effective at blocking the initial autoprocessing of full-length Gag-Pol in HIV-1-infected T cells. Thus, we have identified at least two HIV-1 protease inhibitors that have activity against the primary autocatalytic step of the embedded HIV-1 protease in Gag-Pol at concentrations that may be attained in HIV-1-infected patients. Due to unique aspects of the initial processing step, it may be possible to develop inhibitors with greater potency against this step, thus halting viral maturation at the earliest stages. The transcription/translation assay could be used to develop more potent inhibitors of this essential first step in viral maturation.

scholarly journals Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

1997 ◽  
Vol 41 (10) ◽  
pp. 2159-2164 ◽  
Author(s):  
A K Patick ◽  
T J Boritzki ◽  
L A Bloom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Drug Combination ◽  
Cellular Cytotoxicity ◽  
Immunodeficiency Virus ◽  
Nelfinavir Mesylate ◽  
Acute Hiv ◽  
Hiv 1

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.

scholarly journals GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1In Vitroand Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

2013 ◽  
Vol 57 (12) ◽  
pp. 6110-6121 ◽  
Author(s):  
Pedro Miguel Salcedo Gómez ◽  
Masayuki Amano ◽  
Sofiya Yashchuk ◽  
Akira Mizuno ◽  
Debananda Das ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Blood Brain Barrier ◽  
Wide Spectrum ◽  
Laboratory Strain ◽  
Cyclic Ether ◽  
Brain Barrier ◽  
Blood Brain ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTWe designed, synthesized, and identified two novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-04810 and GRL-05010, containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand,bis-tetrahydrofuranylurethane (bis-THF), and a difluoride moiety, both of which are active against the laboratory strain HIV-1LAI(50% effective concentrations [EC50s], 0.0008 and 0.003 μM, respectively) with minimal cytotoxicity (50% cytotoxic concentrations [CC50s], 17.5 and 37.0 μM, respectively, in CD4+MT-2 cells). The two compounds were active against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to various antiviral regimens. GRL-04810 and GRL-05010 also blocked the infectivity and replication of each of the HIV-1NL4-3variants selected by up to 5 μM lopinavir (EC50s, 0.03 and 0.03 μM, respectively) and atazanavir (EC50s, 0.02 and 0.04 μM, respectively). Moreover, they were active against darunavir (DRV)-resistant variants (EC50in 0.03 to 0.034 μM range for GRL-04810 and 0.026 to 0.043 μM for GRL-05010), while DRV had EC50s between 0.02 and 0.174 μM. GRL-04810 had a favorable lipophilicity profile as determined with the partition (logP) and distribution (logD) coefficients of −0.14 and −0.29, respectively. Thein vitroblood-brain barrier (BBB) permeability assay revealed that GRL-04810 and GRL-05010 may have a greater advantage in terms of crossing the BBB than the currently available PIs, with apparent penetration indexes of 47.8 × 10−6and 61.8 × 10−6cm/s, respectively. The present data demonstrate that GRL-04810 and GRL-05010 exert efficient activity against a wide spectrum of HIV-1 variantsin vitroand suggest that two fluorine atoms added to theirbis-THF moieties may well enhance their penetration across the BBB.

scholarly journals Wide variation in susceptibility of transmitted/founder HIV-1 subtype C Isolates to protease inhibitors and association with in vitro replication efficiency

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Katherine A. Sutherland ◽  
Dami A. Collier ◽  
Daniel T. Claiborne ◽  
Jessica L. Prince ◽  
Martin J. Deymier ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Subtype C ◽  
Replication Efficiency ◽  
In Vitro Replication ◽  
Hiv 1

Non-Competitive Protein Phosphatase-1 Inhibitors Prevent Sickling of SS RBCs.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4038-4038
Author(s):  
Jerod Hairston ◽  
Keon Combi ◽  
Altreisha Foster ◽  
Bak Kim ◽  
Victor R. Gordeuk ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Cultured Cells ◽  
Conflicts Of Interest ◽  
Protein Phosphatase 1 ◽  
Cell Protein ◽  
Trypan Blue Exclusion ◽  
Future Design ◽  
Small Molecular Inhibitors ◽  
Hiv 1

Abstract Abstract 4038 Poster Board III-974 Protein phosphatase-1 (PP1) has been implicated in the regulation of KCC (K:Cl) transporters, which transport K+ and Cl- ions from red blood cells (RBCs) and in the setting of sickle cell disease may contribute to RBC dehydration and sickling. We have studied host cell protein phosphatase-1 (PP1) in the context of HIV-1 replication and designed novel small molecule non-competitive inhibitors of PP1 that are efficient in the inhibition of HIV-1 but not toxic for cultured cells. We analyzed the effect of our novel non-competitive PP1 inhibitors and the conventional competitive PP1 inhibitor, ocadaic acid, on the sickling of hemoglobin SS RBCs in vitro. We cultured hemoglobin SS RBCs overnight at 1% O2 in the presence of the PP1 inhibitors and then photographed the RBCs and counted the percentage of sickled RBCs. We found that the non-competitive PP1 inhibitor, 1E7-04 prevented RBC sickling by 40% at 10 mM concentration. The 1E7-04 was not toxic at 10 mM concentration for cultured CEM T cells as determined by trypan blue exclusion assay using an automatic cell counter. Our study suggests that small molecular inhibitors of PP1 might be candidates for the future design of anti-sickling drugs. Acknowledgments. This work was supported by NHLBI grant U54HL090508-02; NHLBI grant R25 HL003679-08 from the National Institute of Helath and The Office of Research on Minority Health and by U.S. Civilian Research & Development Foundation grant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 4′-C-Methyl-2′-Deoxyadenosine and 4′-C-Ethyl-2′-Deoxyadenosine Inhibit HIV-1 Replication

2011 ◽  
Vol 55 (5) ◽  
pp. 2379-2389 ◽  
Author(s):  
B. Christie Vu ◽  
Paul L. Boyer ◽  
Maqbool A. Siddiqui ◽  
Victor E. Marquez ◽  
Stephen H. Hughes
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Cultured Cells ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Viral Dna ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTIt is important to develop new anti-HIV drugs that are effective against the existing drug-resistant mutants. Because the excision mechanism is an important pathway for resistance to nucleoside analogs, we are preparing analogs that retain a 3′-OH and can be extended after they are incorporated by the viral reverse transcriptase. We show that 4′-C-alkyl-deoxyadenosine (4′-C-alkyl-dA) compounds can be phosphorylated in cultured cells and can inhibit the replication of HIV-1 vectors: 4′-C-methyl- and 4′-C-ethyl-dA show both efficacy and selectivity against HIV-1. The compounds are also effective against viruses that replicate using reverse transcriptases (RTs) that carry nucleoside reverse transcriptase inhibitor resistance mutations, with the exception of the M184V mutant. Analysis of viral DNA synthesis in infected cells showed that viral DNA synthesis is blocked by the incorporation of either 4′-C-methyl- or 4′-C-ethyl-2′-deoxyadenosine.In vitroexperiments with purified HIV-1 RT showed that 4′-C-methyl-2′-dATP can compete with dATP and that incorporation of the analog causes pausing in DNA synthesis. The 4′-C-ethyl compound also competes with dATP and shows a differential ability to block DNA synthesis on RNA and DNA templates. Experiments that measure the ability of the compounds to block DNA synthesis in infected cells suggest that this differential block to DNA synthesis also occurs in infected cells.

Synthesis of N-glyoxylyl peptides and their in vitro evaluation as HIV-1 protease inhibitors

1997 ◽  
Vol 5 (4) ◽  
pp. 707-714 ◽  
Author(s):  
Driss Qasmi ◽  
Eve de Rosny ◽  
Loïc René ◽  
Bernard Badet ◽  
Isabelle Vergely ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
In Vitro Evaluation ◽  
Glyoxylyl Peptides ◽  
Hiv 1

scholarly journals In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors

2008 ◽  
Vol 52 (4) ◽  
pp. 1545-1548 ◽  
Author(s):  
Delphine Desbois ◽  
Bénédicte Roquebert ◽  
Gilles Peytavin ◽  
Florence Damond ◽  
Gilles Collin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Phenotypic Susceptibility

ABSTRACT We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.

scholarly journals Molecular insights into the inhibition of plasmepsins by HIV-1 protease inhibitors: Implications for antimalarial drug discovery

2021 ◽  
Author(s):  
Vandana Mishra ◽  
Ishan Rathore ◽  
Anuradha Deshmukh ◽  
Swati Patankar ◽  
Alla Gustchina ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Ic50 Values ◽  
Multiple Regions ◽  
Potential Drug Targets ◽  
Hiv 1 ◽  
Micromolar Range

Malaria is a deadly disease, and the worldwide emergence of drug resistance in the Plasmodium parasites demands the development of novel and potent antimalarials. HIV-1 protease inhibitors (HIV-1 PIs) alleviate the Plasmodium pathogenesis during malaria/HIV-1 co-infection plausibly by inhibiting vacuolar plasmepsins (PMs), the hemoglobin degrading proteases from P. falciparum. All five FDA-approved HIV-1 PIs tested against PMII exhibit the Ki values in the low micromolar range of which RTV and LPV display the highest inhibition activity. Both inhibitors impede in vitro growth of P. falciparum at low micromolar IC50 values. We report the first crystal structures of PMII complexed with RTV and LPV that reveal the binding mode and interactions of the inhibitors in the active site as well as elucidate the mechanism underlying their differential potency. The conformational flexibility of the P4 group in RTV allows it to explore multiple regions of the S4 pocket. The present study establishes vacuolar PMs as potential drug targets of HIV-1 PIs. The molecular details explaining the inhibitory mechanism of HIV-1 PIs might be crucial in designing novel and potent antimalarial analogs. This work strengthens the prospect of drug repurposing as an alternative strategy towards antimalarial treatments and provides an opportunity to tackle malaria and HIV-1 co-infection.

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