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

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 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.

Inhibition by desferrioxamine of in-vitro replication of HIV-1

The Lancet ◽  
1991 ◽  
Vol 337 (8744) ◽  
pp. 795 ◽  
Author(s):  
Edward Tabor ◽  
JayS Epstein ◽  
IndiraK Hewlett ◽  
SherwinF Lee
Keyword(s):  
In Vitro Replication ◽  
Hiv 1

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

Binding Free Energy Calculations of Nine FDA-approved Protease Inhibitors Against HIV-1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

2016 ◽  
Vol 87 (4) ◽  
pp. 487-498 ◽  
Author(s):  
Husain A. Lockhat ◽  
José R. A. Silva ◽  
Cláudio N. Alves ◽  
Thavendran Govender ◽  
Jerônimo Lameira ◽  
...  
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Protease Inhibitors ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Subtype C ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Hiv 1
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