Inhibiting the Dimerization of HIV-1 Protease

Zutshi, Reena; Shultz, Michael D.; Lutgring, Ray; Bishop, Patricia A.; Schweitzer, Barbara A.; Vogel, Karen; Franciskovich, Jeff; Wilson, Matthew E.; Chmielewski, Jean

doi:10.1055/s-1998-1854

Cited by 10 publications

(3 citation statements)

References 8 publications

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“…For instance, 1 a has a remarkable K i value of 220 n M . Peptide 1 b , in which TrpOH has been replaced with PheNH 2 , is an even better inhibitor, with a threefold increase in activity 7. A key aspect of the system is the length of the tether: 14 CH 2 units appears to be the most appropriate length for placing the amino termini of the two peptides approximately 10 Å apart, which is the distance found between the N and C termini of each monomer in the enzyme 8…”

Section: Methodsmentioning

confidence: 99%

Allosteric Regulation of an HIV-1 Protease Inhibitor by ZnII Ions

Valente

Gobbo²,

Licini

et al. 2001

Angew. Chem.

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Allosteric regulation of protein activity by noncovalent modifiers (ions or neutral molecules) is a feature found in many natural systems including enzymes. [1] The role of these modifiers is to induce conformational changes in the protein that trigger its activity while they are usually not directly involved in the specific function performed by the macromolecule. and 2.5 equiv of SmI 2 ) when, after 30 min, excess SmI 2 was eliminated from the reaction mixture by bubbling a stream of air prior to the hydrolysis.After formation of the alkyl (2E,4E)-2-alkylalka-2,4-dienoate 4, the SmI 2 -promoted 1,4-reduction of the two conjugated CÀC double bonds, which is initiated by oxidative addition of SmI 2 , produces an enolate radical 5, [12] which could explain the observed dimerization at the d-position of compounds 4 a, and 4 e. A second electron transfer from SmI 2 affords an allylic dianion 6 and its hydrolysis with H 2 O or D 2 O produces the corresponding compound 2 (Scheme 1).The observed lower diastereoselectivity in the formation of the CÀC double bond in the synthesis of 2 a and 2 e, neither of which contain a-alkyl substituents, may be explained by assuming that in case of the a-alkylated esters 2 b ± d and 2 f ± i the s-cis conformation of the starting diene is disfavored by steric hindrance produced by the substitution at the a-carbon atom, while the 1,4-reduction of the conjugated CÀC double bonds of 2 a and 2 e takes place through both the s-cis and s-trans conformations. The complete deuteration at C5 instead of at C3 of the dianion 6 could be explained by assuming that in this resonance-stabilized dianion, the 1,4dianion structure is more stable than the 1,2-dianion structure due to the charge repulsions.The proposed mechanism is supported by the fact that the synthesis of compounds 2 can be also carried out starting from the corresponding alkyl (2E,4E)-2-alkylalka-2,4-dienoate 4. Thus, treatment of ethyl (2E,4E)-2-hexylhexa-2,4-dienoate (4 d) with SmI 2 (2.5 equiv) and D 2 O (2 mL) for 30 min at room temperature affords 2 d in 84 % yield.The described methodology can be applied to obtain ddeuterio-b,g-unsaturated esters. The reaction of 2 h with LDA, followed by treatment with H 2 O afforded ethyl (E)-5deuterio-2-methyl-5-phenylpent-3-enoate (8 h) with total diastereoselectivity (89 % yield). Taking into account that the CÀC double bond of d-deuterio-and a,d-dideuterio-b,gunsaturated esters can be easily hydrogenated, [13] the proposed methodology can be used to prepare saturated ddeuterio-and a,d-dideuterioesters, respectively.In conclusion, in the presence of D 2 O, the simple SmI 2promoted elimination/reduction sequence provides an efficient method for synthesizing a,d-dideuterio-b,g-unsaturated esters 2, in which the CÀC double bond is generated with total or high diastereoselectivity, starting from the readily available a-halo-b-hydroxy-g,d-unsaturated esters 1. Experimental SectionGeneral procedure: A solution of SmI 2 (2.3 mmol) in THF (24 mL) was slowly added dropwise, under a nitrogen atmo...

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Section: Methodsmentioning

confidence: 99%

Allosteric Regulation of an HIV-1 Protease Inhibitor by ZnII Ions

Valente

Gobbo²,

Licini

et al. 2001

Angew. Chem.

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“…Truncation of the parent compound 1 by three residues had no effect on the mechanism of inhibition, as parallel lines were also obtained for the truncated inhibitor 2. [18] This modification was also incorporated into compounds 5 and 6 in an attempt to increase potency (7 d and 8 d, respectively). In contrast, larger shifts in the slope were obtained with the smallest inhibitors 5 and 6 ( Figure 2 c), indicating a change in the mechanism of inhibition.…”

Section: Small-molecule Inhibitors Of Hiv-1 Protease Dimerization Dermentioning

confidence: 99%

Small-Molecule Inhibitors of HIV-1 Protease Dimerization Derived from Cross-Linked Interfacial Peptides

et al. 2000

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Die kleinste Struktur, die erforderlich ist, um die Dimerisierung von HIV‐1‐Protease zu inhibieren, wurde erhalten durch Entfernen einiger Reste von den N‐Termini der Peptidketten eines bekannten Inhibitors (Ki=220±10 nM), der durch Verknüpfung der N‐Termini von Peptiden aus dem Wechselwirkungsbereich der HIV‐Protease über einen Linker erhalten wurde, und anschließendes Ersetzen des Trp‐OH‐Restes gegen Phe‐NH2. Molecular‐Modeling‐Untersuchungen an der erhaltenen Struktur führten zu 1, das die HIV‐1‐Protease über einen Dissoziationsmechanismus inhibiert und damit ein idealer Ausgangspunkt für die Identifizierung noch aktiverer Reagentien ist.

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“…Previous experiments in our laboratory had found that replacing the Trp-OH residue of 1 with Phe-NH 2 led to a threefold increase in HIV-1 protease inhibition. [18] This modification was also incorporated into compounds 5 and 6 in an attempt to increase potency (7 d and 8 d, respectively). With both compounds this change led to approximately a twofold increase in inhibition (Table 1).…”

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confidence: 99%