Role of Human Immunodeficiency Virus (HIV) Type 1 Envelope in the Anti-HIV Activity of the Betulinic Acid Derivative IC9564

Holz-Smith, Sonia; Sun, I‐Chen; Jin, Lei; Matthews, Thomas J.; Lee, Kuo‐Hsiung; Chen, Chin Ho

doi:10.1128/aac.45.1.60-66.2001

Cited by 82 publications

(84 citation statements)

References 43 publications

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“…The human T lymphoblastoid cell lines, CEM and MT4, were maintained in RPMI 1640 medium containing 10% FBS and 100 units͞ml penicillin and streptomycin. The construction and characterization of the chimeric virus NLDH120 has been described (24). The selection and characterization of the neutralization-resistant DH012mu virus was also reported recently (6).…”

Section: Methodsmentioning

confidence: 99%

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The role of the third β strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012

Zhu

Holz-Smith

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Neutralization of HIV-1 primary isolates has been a tremendous challenge for AIDS vaccine development. Here, we identify a single amino acid change (T198P) in gp120 that alters the neutralization sensitivity of the primary isolate DH012 to antibodies against multiple neutralization epitopes that include the V3, CD4-induced, and CD4 binding sites in gp120. This mutation is located in the V1͞V2 stem region that forms the third ␤ strand (␤3) of the bridging sheet of gp120. The conformation of variable loops, especially V1͞V2 and V3, was proposed to regulate the accessibility of these neutralization epitopes. The results of this study indicate a direct association between the V1͞V2 and V3 loops of DH012 gp120. The single amino acid mutation T198P in the ␤3 severely compromises the interaction between the V1͞V2 and V3 loops. These results suggest that interaction of V1͞V2 and V3 can mask the neutralization epitopes and that the ␤3 plays a critical role in determining the neutralization sensitivity by modulating the interaction. This study provides an insight into why primary isolates are relatively resistant to antibody neutralization and might facilitate the development of anti-HIV strategies against HIV-1 infection.

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Section: Methodsmentioning

confidence: 99%

“…DH012mu is the virus that grows in the presence of C1206 at 100-fold dilution. The detailed protocol for the neutralization has been described (24,25). Normal human serum (NHS) was included in the assay as a negative control.…”

Section: Development and Mutations Of Neutralization-resistant Dh012mentioning

confidence: 99%

The role of the third β strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012

Zhu

Holz-Smith

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…The second group of anti-HIV active compounds are 28-amides Soler et al, 1996;Sun et al, 2002) of betulinic acid that block the entry of the virion into cells. The most important amide derivatives (Holz-Smith et al, 2001;Sun et al, 2002) are compounds 9 and 10 also known as RPR103611 and IC9564. The third group is represented by compounds that combine both of the previously mentioned mechanizms of activity (Huang et al, 2006) because they contain a combination of both pharmacophors -acyl group in the position 3 and 28-amide group.…”

Section: Overview Of Other Biological Activities Of Acidmentioning

confidence: 99%

The Potential of Triterpenoids in the Treatment of Melanoma

Šarek¹,

Kvasnica²,

Vlk³

et al. 2011

Research on Melanoma - A Glimpse Into Current Directions and Future Trends

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“…1). For example, betuliniyl aminooctanoylamino-3R-hydroxy-6-methylheptanoic acid (IC9564), which has a side chain at position 28 of betulinic acid, is a potent HIV-1 entry inhibitor (5). In contrast, dimethyl-succinyl-betulinic acid (DSB), which has a side chain at position 3, exhibits potent anti-HIV activity by inhibiting the maturation of the viral progeny (4, 7).…”

mentioning

confidence: 99%

“…The anti-HIV activity of these compounds was evaluated with an HIV-1 infectivity assay described previously (5). A diluted HIV-1 stock at a multiplicity of infection of 0.001 50% tissue culture infective dose per cell was used to infect MT4 cells in the presence of various concentrations of the compounds.…”

mentioning

confidence: 99%

Bifunctional Anti-Human Immunodeficiency Virus Type 1 Small Molecules with Two Novel Mechanisms of Action

Huang

Yuan

Aiken

et al. 2004

Antimicrob Agents Chemother

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A class of betulinic acid derivatives was synthesized to target two critical steps in the human immunodeficiency virus type 1 (HIV-1) replication cycle, entry and maturation. Each mechanism of HIV-1 inhibition is distinct from clinically available anti-HIV therapeutics. The viral determinants of the antientry and antimaturation activities are the bridging sheet of HIV-1 gp120 and the P24/p2 cleavage site, respectively.Betulinic acid derivatives are a class of small molecules that exhibit anti-human immunodeficiency virus type 1 (anti-HIV-1) activity (6,7,11). The targets of betulinic acid derivatives are varied, depending primarily on the side chain structures of the compounds (6) (Fig. 1). For example, betuliniyl aminooctanoylamino-3R-hydroxy-6-methylheptanoic acid (IC9564), which has a side chain at position 28 of betulinic acid, is a potent HIV-1 entry inhibitor (5). In contrast, dimethyl-succinyl-betulinic acid (DSB), which has a side chain at position 3, exhibits potent anti-HIV activity by inhibiting the maturation of the viral progeny (4, 7). IC9564 and DSB share a five-membered betulinic acid ring structure. Based on the molecular targets and chemical structures of IC9564 and DSB, we synthesized a class of compounds possessing both of these structural features, which resulted in an anti-HIV-1 profile superior to those of leucine (LH15) and N- [3-O-(3Ј,3Ј-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-11-aminoundecanoic acid (LH55) are two of these compounds with potent anti-HIV activity.Synthesis and anti-HIV-1 activity of bifunctional small molecules LH15 and LH55. The protocol used to synthesize LH15 and LH55 was modified from previously described procedures (4, 12). The antientry functional groups, leucine and aminoundecanoic acid methyl esters, were introduced into the backbone of betulinic acid at position 28. The resulting intermediates were refluxed with 2,2-dimethylsuccinic anhydride in the presence of pyridine and dimethylaminopyridine to introduce the antimaturation side chains at position 3. The final products were purified with high-performance liquid chromatography to yield LH15 and LH55.1 H nuclear magnetic resonance with signal assignment and mass spectrometry were performed to verify the structures.The anti-HIV activity of these compounds was evaluated with an HIV-1 infectivity assay described previously (5). A diluted HIV-1 stock at a multiplicity of infection of 0.001 50% tissue culture infective dose per cell was used to infect MT4 cells in the presence of various concentrations of the compounds. The compounds IC9564 and DSB (4, 5) inhibit various HIV-1 isolates at submicromolar concentrations but not the protease inhibitor-resistant strain PI-R, which is less sensitive to DSB (Table 1). LH15 and LH55, in general, are at least a log more potent than either IC9564 or DSB. The results shown in Table 1 also demonstrate that LH15 and LH55 are potent inhibitors of the multiple-protease-inhibitor-resistant strain PI-R (2) and the multiple-reverse transcriptase (RT)-inhibitorresistant strain RTI-R (...

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Role of Human Immunodeficiency Virus (HIV) Type 1 Envelope in the Anti-HIV Activity of the Betulinic Acid Derivative IC9564

Cited by 82 publications

References 43 publications

The role of the third β strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012

The role of the third β strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012

The Potential of Triterpenoids in the Treatment of Melanoma

Bifunctional Anti-Human Immunodeficiency Virus Type 1 Small Molecules with Two Novel Mechanisms of Action

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