Rational Design of Peptide-Based HIV Proteinase Inhibitors

Roberts, Noel A.; Martin, Joseph A.; Kinchington, D.; Broadhurst, Anne V.; Craig, Jane; Duncan, I. B. R.; Galpin, S.; Handa, B.K.; Kay, John; Kröhn, Anthony

doi:10.1126/science.2183354

Cited by 933 publications

(486 citation statements)

References 22 publications

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“…This conv,srsion was slow initially (within the first 24 L-I) but accelerated thereafter (to be complete between 24 and 30 h), reminiscem of an autocatalytic reaction. A parallel incubation was thus performed in the presence of 100 nM Ro31-8959, an inhibitor that is completely specific for HlV PR [14]. No conversion occurred under these conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic activity of precursor forms of HIV‐1 proteinase

et al. 1992

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The wild-type -Phe*Pro-bond located at the N-terminus of the mature aspnrtic protcinasc of HIV-l was repluccd by -llc-Pro-or -V&Pro-. By this means, processing at this clcavngc junction was prevented and so. extended or precursor fcxs of HIV-protcinase were gcncmted. Thcsc constructs were expressed in ~xchcricl~iu cofi. purified therefrom, and their specificity. activity ut different pH values and susceptibility to the potent inhibitor, Ro3 l-8959, was assessed, A hitherto unobserved cleavage junction (at -Alu-Phe*Lcu-Gin-)in the frame-shift region of the gag-p01 viral genome was identified and contirmcd by demonstrating clcnvagc of a synthetic pcptide corresponding to this region. The implications for viral replication of self-processing at neutral pH by proteinase whilst still present (in a prccuisur tjrm) as a component of the polyprotcin arc considered; such reactions, however, are still blocked cvcn at pH values us high us 8.0 by Ro3 l-8959.HIV-proteinase precursor; Activity and pH dcpcndcnce; Inhibition by Ro31-8959; Novel polyprotein clcuvagc junction

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Section: Resultsmentioning

confidence: 99%

Intrinsic activity of precursor forms of HIV‐1 proteinase

et al. 1992

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“…However, the R configuration reported here is equivalent to S in the inhibitors mentioned above, with the difference being the result of the nomenclature only. It should also be kept in mind that the R configuration results in better binding for some short inhibitors with a hydroxyethylene insert, with a different binding mode (Krohn et al, 1991;Roberts et al, 1990). map.…”

Section: I F O Imentioning

confidence: 99%

Crystal structure of a complex of HIV‐1 protease with a dihydroxyethylene‐containing inhibitor: Comparisons with molecular modeling

Thanki¹,

Rao²,

Foundling³

et al. 1992

Protein Science

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The structure of a crystal complex of recombinant human immunodeficiency virus type 1 (HIV-1) protease with a peptide-mimetic inhibitor containing a dihydroxyethylene isostere insert replacing the scissile bond has been de- The bound inhibitor diastereomer has the R configurations at both of the hydroxyl chiral carbon atoms. One of the diol hydroxyl groups is positioned such that it forms hydrogen bonds with both the active site aspartates, whereas the other interacts with only one of them. Comparison of this X-ray structure with a model-built structure of the inhibitor, published earlier, reveals similar positioning of the backbone atoms and of the side-chain atoms in the P2-P2' region, where the interaction with the protein is strongest. However, the X-ray structure and the model differ considerably in the location of the P3 and P3' end groups, and also in the positioning of the second of the two central hydroxyl groups. Reconstruction of the central portion of the model revealed the source of the hydroxyl discrepancy, which, when corrected, provided a PI-PI' geometry very close to that seen in the X-ray structure.

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“…HIV protease inhibitors (PIs) have revolutionized the treatment of HIV infection (Roberts et al, 1990;Vacca et al, 1994;Danner et al, 1995;Kempf et al, 1995;Patick et al, 1996). Due to limited oral bioavailability and poor pharmacokinetics of many of the currently available PIs, additional efforts have been made to design more potent PIs with improved pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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Rational Design of Peptide-Based HIV Proteinase Inhibitors

Cited by 933 publications

References 22 publications

Intrinsic activity of precursor forms of HIV‐1 proteinase

Intrinsic activity of precursor forms of HIV‐1 proteinase

Crystal structure of a complex of HIV‐1 protease with a dihydroxyethylene‐containing inhibitor: Comparisons with molecular modeling

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

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