A CD4 mimic as an HIV entry inhibitor: Pharmacokinetics

Hashimoto, Chie; Narumi, Tetsuo; Otsuki, Hiroyuki; Hirota, Yuki; Arai, Hiroshi; Yoshimura, Kazuhisa; Harada, Shigeyoshi; Ohashi, Nobukimi; Nomura, Wataru; Miura, Tomoyuki; Igarashi, Tatsuhiko; Matsushita, Shuzo; Tamamura, Hirokazu

doi:10.1016/j.bmc.2013.10.005

Cited by 18 publications

(33 citation statements)

References 29 publications

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“…In 2005, using the targeted screening approach of chemical libraries, we identified two test compounds-NBD-556 and NBD-557-that were capable of preventing syncytia in a cell-cell fusion assay (14). The compounds also inhibited a panel of laboratory-adapted and primary isolates with low-micromolar potency, a discovery that led to additional studies from several research groups (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) that uncovered the binding mechanism of these small-molecule inhibitors and their subsequent effect on the conformation of gp120. The binding of these molecules to the Phe43 cavity was confirmed in biophysical and resistant mutant studies (24,25,27); other studies also have shown that these compounds of only about 337 Da in size are capable of inducing conformational changes in gp120 (24,25).…”

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confidence: 99%

Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study

Curreli

Kwon

Zhang

et al. 2014

Antimicrob Agents Chemother

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We previously identified two small-molecule CD4 mimetics-NBD-556 and NBD-557-and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at ϳ2-Å resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists.

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confidence: 99%

Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study

Curreli

Kwon

Zhang

et al. 2014

Antimicrob Agents Chemother

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“…Amine 15 was coupledw ith Boc-glycine to yield aB oc-protected amine (17), followed by Boc deprotection to yield free amine 18,w hichw as converted by amidinylation into guanidino compound 19.A mine 15 was also coupled with N-Boc-5aminovaleric acid to yield aBoc-protected amine (20), followed by Boc deprotection to yield free amine 21.T his amine (21) was converted by amidinylation into ag uanidinoc ompound (22). Finally,a mine 15 was cyanomethylated to yield the bis-nitrilo amine or diacetonitrile (23), followed by reduction to yield tetra-amine 24,w hich was convertedb ya midinylation into the corresponding diguanidino compound (25).…”

Section: Resultsmentioning

confidence: 99%

“…The anti-HIV activities of the synthetic compounds were evaluated against an R5 primary isolate YTAs train. [21][22][23][24][25][26]29] The cytotoxicityo ft he compounds was also evaluated by determining the viability of mock-infected PM1/CCR5 or TZM-blc ells (for details, see Experimental Section).…”

Section: Antiviral Activity and Cytotoxicitymentioning

confidence: 99%

“…[6][7][8][9][10][11] Additionally,s ome small compounds such as BMS-378806, [12] IC-9564 [13] and NBDs [14] have been identified that bind to gp120 and inhibitt he formation of the key protein-protein interaction betweeng p120 and CD4 and consequently viral attachment. Recently,s everal small-molecule CD4 mimics, which competitivelys uppress the binding of gp120 to CD4, [15][16][17][18][19][20][21][22][23][24][25][26] have been developed as an ovel class of HIV entry inhibitors. [27][28][29][30] The interaction of these CD4 mimics with ac onserved gp120 pocket, designated as the "Phe43 cavity", causesc onformational changes in gp120 [27,28] and also favorable enthalpy change as observed in the binding of soluble CD4 to gp120.…”

Section: Introductionmentioning

confidence: 99%

“…[29] Based on the first reported CD4 mimic, NBD-556 (1), [14] we have found YYA-021 with relativelyh igha nti-HIV activity and low cytotoxicity,a nd HAR-171 (2), which has two cyclohexyl groups as spiro attachments to the piperidiner ing, with high anti-HIV activity ( Figure 1). [21][22][23][24][25][26] Molecular modeling of HAR-171…”

Section: Introductionmentioning

confidence: 99%

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Small‐Molecule CD4 Mimics Containing Mono‐cyclohexyl Moieties as HIV Entry Inhibitors

et al. 2016

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CD4 mimics are small molecules that inhibit the protein-protein interaction between gp120 and CD4, which is a key interaction for the entry of human immunodeficiency virus (HIV) into host immune cells. In the present study, mono-cyclohexyl-type CD4 mimics were designed to form hydrophobic and electrostatic interactions with Val430 and Asp368 located in the entrance of the Phe43 cavity of gp120, the interaction site of CD4. YIR-329, a novel 1-azaspiro[5.5]undecane derivative with a cyclohexyl ring attached to the piperidine ring, exhibited only slightly weaker anti-HIV activity than a previously described lead HAR-171, and modeling results indicated the formation of advantageous interactions by the para-chlorophenyl moiety of YIR-329. To introduce an electrostatic interaction with Asp368, derivatives with a guanidino group on the piperidine nitrogen atom were synthesized. Mono-cyclohexyl-type CD4 mimics with a guanidino group, such as YIR-819 (N(1) -(4-chlorophenyl)-N(2) -(1-(2-(N-(amidino)glycinamide)ethyl)-2-cyclohexylpiperidin-4-yl)oxalamide) and YIR-821 (1-(2-(5-guanidinovaleramide)ethyl derivative of YIR-819), were identified that exhibit approximately fivefold more potent anti-HIV activity than YIR-329. In combination with a neutralizing antibody, their anti-HIV activities were augmenting. Modeling results suggest that these compounds interact effectively with Val430 and either Asp368 or Asp474 in the gp120 Phe43 cavity. YIR-819 and YIR-821 represent useful lead compounds for the further development of HIV-1 entry inhibitors and could potentially be useful for co-administration with neutralizing antibodies for the treatment of HIV infection and AIDS.

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Cumyl Hydroperoxide‐Promoted Oxidative Amidation of 2‐Oxoaldehydes with Amines under Metal‐Free Conditions for the Synthesis of Unsymmetrical Oxamides

et al. 2015

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A CD4 mimic as an HIV entry inhibitor: Pharmacokinetics

Cited by 18 publications

References 29 publications

Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study

Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study

Small‐Molecule CD4 Mimics Containing Mono‐cyclohexyl Moieties as HIV Entry Inhibitors

Cumyl Hydroperoxide‐Promoted Oxidative Amidation of 2‐Oxoaldehydes with Amines under Metal‐Free Conditions for the Synthesis of Unsymmetrical Oxamides

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