HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols

Budt, Karl-Heinz; Peyman, Anusch; Hansen, Jutta; Knolle, Jochen; Meichsner, C; Paessens, Arno; Ruppert, Dieter; Stowasser, Bernd

doi:10.1016/0968-0896(95)00069-s

Cited by 21 publications

(24 citation statements)

References 31 publications

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“…The crystal structure of one member of this class of compounds, HOE/BAY 793, complexed to the HIV-1 protease is consistent with the structureelactivity relationship observed for these inhibitors assuming (a) that the different members of this class bind in essentially the same binding mode and (b) that the individual substituents can be varied independently. Budt et al (1995) reported that the stereochemistry of the carbons in the central diol unit (RR, RS, SS) does not appear to influence the inhibition of the protease significantly. The results of recent modeling studies based on the orthorhombic X-ray structure described here, suggest that the different diol central units can rearrange themselves to fit into the active site.…”

Section: Discussionmentioning

confidence: 99%

“…The class of inhibitors discussed here, contains vicinal diols as their central building block. To optimize the inhibition at the enzyme level and in v i m antiviral activity, we have previously reported on a substantial number of different compounds with vicinal diols as the central unit (Budt et al, , 1995. The crystal structure of one member of this class of compounds, HOE/BAY 793, complexed to the HIV-1 protease is consistent with the structureelactivity relationship observed for these inhibitors assuming (a) that the different members of this class bind in essentially the same binding mode and (b) that the individual substituents can be varied independently.…”

Section: Discussionmentioning

confidence: 99%

“…HOE/BAY 793 is a potent inhibitor of HIV replication in vitro. It inhibits the HIV-1 protease with an IC,, of 0.3 nM (Budt et al, 1995). In cell culture experiments, it is highly active against HlV-1 with an EC,,, of 3 nM.…”

mentioning

confidence: 91%

“…The structure/activity relationship (Budt et al, 1995) of the vicinal-diol class of compounds to which HOE/ BAY 793 belongs will be discussed, based on the work presented in this paper. In particular, we report on the interaction of the central 1,2-dihydroxyethylene unit with the HIV-1 protease and the contribution of the additional CH(0H) moiety to the improved inhibition compared to the same inhibitor type with a central hydroxymethylene group .…”

mentioning

confidence: 99%

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Structure of HOE/BAY 793 Complexed to Human Immunodeficiency Virus (HIV‐1) Protease in Two Different Crystal Forms Structure/Function Relationship and Influence of Crystal Packing

Lange-Savage¹,

Berchtold²,

Liesum³

et al. 1997

European Journal of Biochemistry

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Human immunodeficiency virus 1 (HIV-1) protease is a prime target in the search for drugs to combat the AIDS virus. The enzyme functions as a C,-symmetric dimer, cleaving the gag and gag-pol viral polyproteins at distinct sites. The possession of a twofold axis passing through the active site, has led to the design of C,-symmetrical inhibitors in the form of substrate-based transition-state analogs. The structure of this inhibitor bound to HIV-1 protease, in two different crystal forms, has been solved at 0.24-nm resolution using X-ray crystallography. In both forms, the details of the inhibitor-protease interactions revealed an overall asymmetric binding mode, especially between the central diol unit and the active-site aspartates. The main binding interactions comprise several specific H-bonds and hydrophobic contacts, which rationalize many of the characteristics of the structure/ activity relationship in the class of vicinal diol inhibitors. In a general analysis of the mobility of the flap regions, which cover the active site and participate directly in binding, using our structures and the HTV protease models present in the Brookhaven databank, we found that in most structures the flexibility of the flaps is limited by local crystal contacts. However, in one of the structures presented here, no significant crystal contacts to the flap regions were present, and as a result the flexibility of the inhibitor bound flaps increased significantly. This suggests that the mobility and conformational flexibility of the flap residues are important in the functioning of HIV-1 protease, and must be considered in the future design of drugs against HIV protease and in structure-based drug design in general.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

mentioning

confidence: 99%

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Structure of HOE/BAY 793 Complexed to Human Immunodeficiency Virus (HIV‐1) Protease in Two Different Crystal Forms Structure/Function Relationship and Influence of Crystal Packing

Lange-Savage¹,

Berchtold²,

Liesum³

et al. 1997

European Journal of Biochemistry

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“…Consequently, these were also examined for their effectiveness toward recombinant cyprosin. HBY-793 (compound 21), which is a symmetrical compound containing a central dihydroxyethylene moiety (38), was found to act as an inhibitor of cyprosin (Table IV). It is, however, much less effective toward the plant enzyme than HIV proteinase or some of the human enzymes for which subnanomolar K i values were obtained.…”

Section: Fig 4 Schematic Representation Of Processing Events In Pmentioning

confidence: 99%

Processing, Activity, and Inhibition of Recombinant Cyprosin, an Aspartic Proteinase from Cardoon (Cynara cardunculus)

White

Cordeiro²,

Arnold

et al. 1999

Journal of Biological Chemistry

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The cDNA encoding the precursor of an aspartic proteinase from the flowers of the cardoon, Cynara cardunculus, was expressed in Pichia pastoris, and the recombinant, mature cyprosin that accumulated in the culture medium was purified and characterized. The resultant mixture of microheterogeneous forms was shown to consist of glycosylated heavy chains (34 or 32 kDa) plus associated light chains with molecular weights in the region of 14,000 -18,000, resulting from excision of most, but not all, of the 104 residues contributed by the unique region known as the plant specific insert. SDS-polyacrylamide gel electrophoresis under non-reducing conditions indicated that disulfide bonding held the heavy and light chains together in the heterodimeric enzyme forms. In contrast, when a construct was expressed in which the nucleotides encoding the 104 residues of the plant specific insert were deleted, the inactive, unprocessed precursor form (procyprosin) accumulated, indicating that the plant-specific insert has a role in ensuring that the nascent polypeptide is folded properly and rendered capable of being activated to generate mature, active proteinase. Kinetic parameters were derived for the hydrolysis of a synthetic peptide substrate by wildtype, recombinant cyprosin at a variety of pH and temperature values and the subsite requirements of the enzyme were mapped using a systematic series of synthetic inhibitors. The significance is discussed of the susceptibility of cyprosin to inhibitors of human immunodeficiency virus proteinase and particularly of renin, some of which were found to have subnanomolar potencies against the plant enzyme.

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Dimerization of Lithiated Terminal Aziridines

Hodgson¹,

Miles²

2006

Angewandte Chemie

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It has been known for a long time that lithiated epoxides 1 (Scheme 1, X = O) can display carbenoid-type reactivity, including dimerization.[1] Such dimerizations have been developed recently by our research group as a synthetic method for the preparation of symmetric 2-ene-1,4-diols 2 (X = O) from terminal epoxides.[2] Although a useful entry to this valuable class of compounds, this method unfortunately displayed only a 2:1 selectivity in favor of the E isomer of the newly formed alkene when using epoxides with primary (R = C 5 H 11 ) or secondary (R = cyclohexyl) alkyl substituents (62 % and 77 % yield of 2-ene-1,4-diol olefin isomer mixtures, respectively).Following on from this, we considered the possibility that lithiated terminal aziridines 1 (X = NPG, PG = protecting group) [3] might undergo similar dimerization, thus leading to synthetically useful (protected) 2-ene-1,4-diamines 2 (X = NPG).[4] At the outset of our studies we were not aware of any examples of such dimerizations in the literature, [5] and it was not known whether the method would yield dimer compounds in useful efficiencies or whether other pathways such as formation of 2H-azirines 3[6] (Scheme 1) would be favored. Although certain lithiated aziridines fused to 5-to 8-membered rings undergo carbenoid transformations, [7] formation of 2H-azirines in these cases would be significantly disfavored because of additional ring strain. There is little precedent for lithiated aziridines having carbenoid reactivity when the aziridine is not fused to a second ring.[7b]One additional variable for aziridines (relative to epoxides) is the choice of the protecting/activating group at the aziridine nitrogen atom. In our initial studies we attempted to dimerize alkyl substituted terminal aziridines bearing the groups Boc (butyloxycarbonyl), tosyl, or Bus (tert-butylsulfonyl), [8] by using lithium 2,2,6,6-tetramethylpiperidide (LTMP) as the base.[3] Upon treatment with this base, the N-Boc-and N-tosyl-protected aziridines gave complex mixtures of products with no dimers observed, but the lithiated NBus-protected aziridine 1 a (X = NBus; R = C 5 H 11 ) formed and underwent dimerization in 90 % yield to give the protected 2-ene-1,4-diamine 2 a (X = NBus; R = C 5 H 11 ) as a mixture of three discernible diastereoisomers.There are only two possible isomers (alkene E and Z isomers) that could arise upon dimerization of an enantiopure terminal aziridine, and so this method seems better suited to enantiopure substrates. With this in mind, we examined the scope of the dimerization reaction with a range of enantiopure (99 % ee) N-Bus-protected terminal aziridines [9] ( Table 1). The enantiopure aziridines (entries 1-5) all dimerized in high efficiency under the same straightforward reaction conditions (aziridine 0.32 mol dm À3 in THF/hexanes (2:3), 3 equiv LTMP, À78 8C to 08C, total reaction time 80 min; see Experimental Section).[10] Crucially, all these reactions proceeded with complete E selectivity for the alkene bond formed, with no traces of the Z alkene ...

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HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols

Cited by 21 publications

References 31 publications

Structure of HOE/BAY 793 Complexed to Human Immunodeficiency Virus (HIV‐1) Protease in Two Different Crystal Forms Structure/Function Relationship and Influence of Crystal Packing

Structure of HOE/BAY 793 Complexed to Human Immunodeficiency Virus (HIV‐1) Protease in Two Different Crystal Forms Structure/Function Relationship and Influence of Crystal Packing

Processing, Activity, and Inhibition of Recombinant Cyprosin, an Aspartic Proteinase from Cardoon (Cynara cardunculus)

Dimerization of Lithiated Terminal Aziridines

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