Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2022 Dec 6;14(1):51–58. doi: 10.1021/acsmedchemlett.2c00376

Structural and Functional Characterization of Indane-Core CD4-Mimetic Compounds Substituted with Heterocyclic Amines

Cheyenne Chaplain †, Christopher J Fritschi †, Saumya Anang ‡, Zhen Gong ∥, Jonathan Richard #,∇, Catherine Bourassa #,∇, Shuaiyi Liang ∥, Mohammadjavad Mohammadi , Jun Park †, Andrés Finzi #,∇, Navid Madani ‡, Joseph G Sodroski ‡,§,○, Cameron F Abrams , Wayne A Hendrickson ∥,⊥, Amos B Smith III †,*
PMCID: PMC9841591  PMID: 36655122

Abstract

graphic file with name ml2c00376_0009.jpg

The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer on the virion surface interacts with the host receptors, CD4 and CCR5/CXCR4, to mediate virus entry into the target cell. CD4-mimetic compounds (CD4mcs) bind the gp120 Env, block CD4 binding, and inactivate Env. Previous studies suggested that a C(5)-methylamino methyl moiety on a lead CD4mc, BNM-III-170, contributed to its antiviral potency. By replacing the C(5) chain with differentially substituted pyrrolidine, piperidine, and piperazine ring systems, guided by structural and computational analyses, we found that the 5-position of BNM-III-170 is remarkably tolerant of a variety of ring sizes and substitutions, both in regard to antiviral activity and sensitization to humoral responses. Crystallographic analyses of representative analogues from the pyrrolidine series revealed the potential for 5-substituents to hydrogen bond with gp120 Env residue Thr 283. Further optimization of these interactions holds promise for the development of CD4mcs with greater potency.

Keywords: HIV, gp120, entry inhibitor, structure-based drug design, X-ray crystallography, antibody-dependent cellular cytotoxicity

The HIV-1 pandemic continues to be a global health issue, with 1.5 million new infections reported by the World Health Organization (WHO) in 2020.1 Encouragingly, of the 38 million individuals infected worldwide, 62% of those living with the disease are receiving some form of treatment.2 However, despite the options available for antiretroviral therapy,3−5 the development of resistance and the requirement for lifelong treatment present challenges for permanent control of HIV-1 infection. Thus, the prevention of HIV-1 transmission remains an elusive goal.

The surface of the HIV-1 virion is decorated with envelope glycoprotein (Env) trimers,6,7 that consist of two noncovalently associated glycoproteins, gp120 and gp41. Env is critical for HIV-1 viral entry into target CD4+ T-cells. When the viral Env interacts with a CD4 receptor on the target cells, a cascade of conformational changes occurs that expose chemokine receptor binding sites on gp120 and prime gp41 for its eventual role in fusing the viral and cell membranes. Subsequent interaction with a chemokine receptor, CCR5 or CXCR4, triggers further conformational changes in Env that lead to viral entry into the host cell.8

In 2016, our laboratory reported a lead CD4-mimetic compound (CD4mc), BNM-III-170 (Figure 1A), possessing low micromolar inhibitory activity against the entry of a range of HIV-1 strains into cells, prompted by the initial discoveries reported by Debnath and co-workers in 2005.10 Crystallographic data of BNM-III-170 and other congeners revealed that such CD4mcs bind to gp120 near the site used by CD4. Specifically, CD4mcs bind in the Phe 43 cavity on the surface of gp120, as well as to the vestibule leading into this cavity (Figure 1B).9 CD4mc binding competitively inhibits CD4 binding and prompts a cascade of conformational changes that mimic those induced by CD4.11 However, in the absence of a target cell expressing CCR5 or CXCR4, this premature activation of Env rapidly leads to irreversible viral inactivation.

Figure 1.

Figure 1

Open in a new tab

(A) Structure of lead CD4mc bis-TFA salt BNM-III-170 (1) with Indane carbons numbered. (B) Cocrystal structure of BNM-III-170 in a gp120C1086 coree monomer with target residues Ala 281, Lys 282, and Thr 283 displayed. A transparent surface was added to show the Phe 43 binding cavity and surrounding vestibule surface.

In our 2016 report, we disclosed an X-ray crystal structure of BNM-III-170 (1) complexed with a gp120 coree protein derived from HIV-1C1086.9 From that structure, it was determined that the optimized CD4mc is in close proximity to the carbonyl of a conserved gp120 residue (Gly 472), via the methylamino-methyl substituent at the 5-position of the Indane scaffold (Figure 1B). Engagement of Gly 472 with native CD4 is known to be associated with moderate restructuring of the Env upon binding.6,12 Pleasingly, introduction of a methylamino-methyl side chain at the 5-position of the Indane scaffold resulted in an increase in viral inhibition as compared to a previously synthesized unsubstituted C(5) congener, DMJ-II-121 (DMJ-II-121: HIV-1JRFL IC50 = 66.8 μM; BNM-III-170: HIV-1JRFL IC50: 9.6 ± 2.9 μM).9

Further examination of the crystal structures of the gp120 coree protein complexed with BNM-III-170 and congeners thereof revealed that the 5-position methylamino methyl side chain approaches toward multiple gp120 residues (Ala 281, Lys 282, Thr 283) that also contribute to the binding of CD4 (Figure 1B).6,12 Since our report on our lead CD4mc (BNM-III-170), extensive SAR optimization of the Indane scaffold has been achieved in our laboratory to target the residues listed above. Fortunately, due to a large-scale process synthesis of BNM-III-170 for animal studies,13−15 a useful intermediate for the construction of different C(5)-amine-containing analogues was available. Specifically, aldehyde 4 (Scheme 1) was available in 12 steps from commercially available 5-bromoindanone (2) and an oxalamide precursor 3. The desired C(5) amines to explore this binding area of gp120 were thus installed via reductive amination of aldehyde 4, followed by TFA deprotection of the Boc protecting groups of intermediate 6, to give the desired TFA salts 7.

Scheme 1. Synthesis of Preliminary Heterocyclic Amine Analogues of BNM-III-170 from the Late-Stage Synthetic Intermediate 4.

Scheme 1

Open in a new tab

Early results demonstrated that the methyl group of the methylamino methyl side chains at C5 could be replaced with a broad range of secondary and tertiary amines; however, few of these replacements resulted in antiviral potency better than that of BNM-III-170. Three compounds from this SAR investigation (7a−c), however, proved of interest (Figure 2). Specifically, C(5)-substituted analogues that replaced the methylamine of BNM-III-170 with a pyrrolidine (7a), piperidine (7b), or piperazine (7c) displayed potency comparable to or better than that of our current lead (BNM-III-170: HIV-1JRFL IC50: 9.6 ± 2.9 μM, A-MLV IC50: > 100 μM).9

Figure 2.

Figure 2

Open in a new tab

Initial CD4mc heterocyclic amine substitutions and bioactivity that inspired further heterocyclic amine incorporation.

With these preliminary data in hand, we further explored the effect of substitution of cyclic amine ring systems at C(5) of the Indane scaffold. It was postulated that saturated heterocyclic rings would serve as ideal templates for functional group substitution, given the highly directional and specific orientations the ring system would impart onto the substituents. Such specific ring conformations could lead to novel interactions with conserved residues in the hydrophobic Envgp120 vestibule, thus improving the potency of our CD4mc. Moreover, given the widespread commercial availability of many enantiomerically pure substituted heterocyclic amines (Scheme 2), there existed the opportunity to generate a diverse analogue library in a manner similar to that of our previous SAR studies.

Scheme 2. Synthesis of Substituted Heterocyclic Amine Analogues of BNM-III-170 from Late-Stage Synthetic Intermediate 4.

Scheme 2

Open in a new tab

Initially, a computational docking screen was performed wherein commercially available heterocyclic amines replaced the lead CD4mc methylamino methyl substituent at the 5-position of the scaffold, as outlined above. Specifically, docking calculations were undertaken for compounds 10a–o (Table 1) using a core monomeric gp120 from HIV-1JRFL. From these calculations, piperidine rings substituted with an amide or carboxylic acid were predicted to have lower or similar free energy of binding to gp120 compared with BNM-III-170, based on GlideScore metrics using an SP scoring function.16 Conversely, addition of an aryl ring as a substituent on a piperazine ring was predicted to be detrimental to the overall ligand-protein interaction profile (Table 1). Additionally, alcohol and amine substituents at various locations on the proposed pyrrolidine rings were suggested to confer favorable binding to gp120. Overall, the computational docking screen suggested that the region being targeted seems to be sensitive to steric effects of large substituents, but may well be tolerant to small hydrophilic substituents placed on a heterocyclic ring.

Table 1. Complete Account of Synthesized and Tested Saturated Heterocyclic Amine Analogues of Lead CD4mc BNM-III-170. IC50 (JRFL) Measurements Were Performed in Triplicatea.

graphic file with name ml2c00376_0007.jpg

graphic file with name ml2c00376_0008.jpg

Open in a new tab
a

In cases where more than one triplicate experiment was performed, values are reported as the average IC50 of the triplicate experiments, followed by the standard error of the mean, and the number (N) of triplicate measurements. None of the compounds inhibited the control virus pseudotyped by the amphotropic murine leukemia virus (A-MLV) Env at concentrations of 100 μM or less. *Compound isolated as a mixture of diastereomers.

Also of interest, many of the computationally docked heterocyclic amine analogues were predicted to maintain hydrogen bonding interactions with residues known to associate with BNM-III-170 (e.g., Gly 473, Met 426), while also engaging residues in previously unexplored chemical space (Glu 429, Asp 477, Asp 474: see Figure S1 for interaction maps of selected analogues generated by Schrödinger’s Maestro suite). Based on the modeling predictions, we undertook synthetic efforts toward the installation of a variety of substituted, saturated 5- and 6-membered heterocyclic amines at the 5-position of the Indane scaffold, following the protocol outlined above (Scheme 2; Supporting Information).

For the saturated 6-membered heterocyclic rings, three piperidines and one piperazine 10a–d were synthesized and evaluated for antiviral activity (Table 1). The heterocyclic amines chosen were guided by computational docking (vide supra) in an effort to validate the in silico modeling. Upon synthesis and evaluation, no improvements in CD4mc potency were observed in comparison to BNM-III-170 for the piperidine and piperazine analogues examined (Table 1). Overall, substitution with a 6-membered heterocyclic amine was associated with a decrease in inhibitory activity. We hypothesize that the bulky 6-membered heterocyclic amines at the Indane scaffold 5-position result in misalignment of the scaffold in the gp120 vestibule and a subsequent decrease in the observed antiviral activity.

Concurrently, a variety of substituted pyrrolidine analogues at the Indane C(5) position were synthesized, which included proline and hydroxy-proline derivatives (Scheme 2, 10e–o). Unlike the saturated 6-membered heterocyclic amines, many of the compounds that contained a pyrrolidine ring displayed low micromolar inhibition of HIV-1JRFL entry (Table 1; 10e–o). Pleasingly, several of the compounds 10e–o exhibited antiviral activity comparable to that of BNM-III-170. Furthermore, substitution at either the 2- or 3-position of the pyrrolidine ring did not display an observable effect on the antiviral activity of this series. Moreover, the GlideScore prediction of structurally related heterocyclic amines provided a reasonable enrichment of suggested substituents, based on the observed IC50 values.

In addition to direct antiviral activity, CD4mcs can “open” Env on HIV-infected cells, thus exposing CD4-induced (CD4i) binding epitopes that would otherwise be occluded. The CD4i epitopes can then be recognized by non-neutralizing antibodies, and thereby permit HIV-infected cell clearance via antibody-dependent cellular cytotoxicity (ADCC).17 We therefore sought to evaluate whether these CD4mcs would also facilitate recognition of HIV-1-infected cells by plasma from HIV-1 infected individuals, as well as mediate ADCC. This could be monitored through a previously described flow cytometry-based assay.17 Compounds that displayed comparable antiviral activity to BNM-III-170 were evaluated first through cell-surface staining for their ability to induce conformational changes that would result in plasma recognition of infected cells. Pleasingly, all compounds (7a, 7c, 10e–f, 10i–j, and 10m–o) were able to mediate plasma binding to HIV-1CH58-infected cells to the same degree as BNM-III-170 (Figure 3A). The compounds were also able to mediate ADCC of CH58-infected cells, as represented in Figure 3B. CD4mcs 7a, 7c, 10e–f, 10i–j, 10m, and 10o were as effective as BNM-III-170, except for CD4mc 10n, which was shown to be less effective at mediating ADCC. Of note, among epimeric pairs of CD4mcs, slight improvements in ADCC activity were observed for the (R) epimers. This effect can be observed for (R)/(S)-3-hydroxypyrrolidine derivatives 10e and 10f as well as (R)/(S)-3-hydroxymethylpyrrolidine derivatives 10i and 10j. These results agree with the observed IC50 values for the epimeric pairs. Overall, all compounds evaluated were able to mediate ADCC as effectively as BNM-III-170 against HIV-1CH58-infected primary CD4+ T cells.

Figure 3.

Figure 3

Open in a new tab

CD4mcs sensitize HIV-1 infected cells to ADCC. Primary CD4 T cells isolated from PBMC were infected with HIV-1CH58TF for 48 h. (A) For cell surface staining, 1:1000 diluted HIV+ plasma (n = 3) was used in the presence of 50 μM of the different CD4mcs, (+)-BNM-III-170, or with equivalent volume of vehicle (DMSO), and an Alexa Fluor 647-conjugated antihuman IgG secondary Ab was then used for fluorescent labeling. (B) For ADCC, infected cells were used as target cells in a FACS-based ADCC assay that measures the killing of infected (p24+) cells to determine their susceptibility to ADCC mediated by a 1:1000 dilution of plasma from 3 HIV-1-infected individuals in the presence of 50 μM different CD4mcs, (+)-BNM-III-170, or with equivalent volume of vehicle (DMSO). (C) Primary CD4 T cells isolated from PBMC were infected with HIV-1JRFL for 48 h. Cell surface staining was performed as described in (A), except at varying concentrations of CD4mc. Error bars indicate means ± standard errors of the means (SEM).

Finally, the CD4mcs were evaluated for their ability to mediate HIV+ plasma binding to tier-2 HIV-1JRFL-infected CD4 primary T-cells (Figure 3C). HIV-1JRFL-infected cells are less sensitive to CD4mc treatment due to a T375S polymorphism in the Phe 43 cavity of the HIV Env. This change renders Env less susceptible to CD4mc compared to Envs having a threonine at residue 375; this is likely due to the capacity of Thr 375 to promote better contacts with the fluoro-chloro-phenyl moiety of the CD4mc compared to a serine at this position.18 Again, we observed that all the CD4mcs were comparable to BNM-III-170, with the exception of 10n which did not effectively mediate HIV+ plasma binding.

To understand the structural basis for these observations, representative compounds of the pyrrolidine series were chosen for cocrystallization with an HIV-1C1086 gp120 coree protein. The selected TFA salts 10j (CJF-II-195) and 10h (CJF-II-197-S) were soaked into preformed crystals of the gp120 coree protein and diffraction data were obtained at 2.77 and 3.07 Å Bragg spacings, respectively (see Supporting Information). These crystals are in space group P212121 with four copies of the gp120-CD4mc complex per asymmetric unit. Diffraction and refinement statistics are reported in Table S1.

As for the gp120 complexes with previous compounds in this series,9,19 the CD4mc entity is associated with gp120 pockets (Figure 4A and B) and hydrogen-bonded to backbone carbonyl groups (Figure 4C–F). In addition to these common hydrogen bonds to gp120 from the CD4mc oxalamide and guanidinium groups, we found for 10j that a hydroxyl group from the heterocyclic amine at the 5-position of the Indane scaffold can also hydrogen bond to the side-chain hydroxyl group of Thr 283 with distances that average 2.9 Å (Figure 4C).

Figure 4.

Figure 4

Open in a new tab

Crystal structures of CD4mcs in complex with gp120 core. (A) Solvent-excluded surface of 10j conformer A in a gp120 core. The surfaces of 10j and the gp120 core are shown in blue and beige, respectively. The transparency of the gp120 core surface was set at 50% so that the surface of 10j within the CD4 binding pocket is visible. Thereby, the blue surface of 10j inserted into the CD4 binding pocket, bounded by a thin black line, is seen through the beige gp120 surface; and the solvent-exposed surface of 10j, bounded by a thick line, remains fully blue. (B) A detailed view of 10j conformer A inserted into the CD4 binding pocket. This view has the complex rotated from Figure 4A by −60° about the x-axis followed by +8° about the y-axis, and the surface of 10j is replaced by a stick representation. (C) Crystal structure of 10j conformer A in a gp120 core. This structure was refined at 2.77 Å resolution. (D) Crystal structure of 10h in a gp120 core. This structure was refined at 3.07 Å resolution. (E) Crystal structure of 10j conformer B in a gp120 core. (F) Bottom view of 10j conformer A in a gp120 core to illustrate water-mediated contacts from 10j to Asn 425.

Further study of the structures of gp120 complexed with 10j revealed that the pyrrolidine moiety adopts two conformations, however, with conformer A (Figure 4C) engaging Thr 283, but with conformer B (Figure 4E) directed away from gp120 interactions. The A conformer predominates (A:B = 0.55:0.45) for two of the complexes in the asymmetric unit, whereas conformer B predominates (A:B = 0.35:0.65) for the other two (Figure S2). Although no significant improvement in viral inhibition was observed with this CD4mc, (Table 1, 10j IC50 HIV-1JRFL: 11.1 μM), our results demonstrate that Thr 283 can be engaged by CD4mcs. Approximately 47% of HIV-1 strains, including HIV-1JRFL used for the antiviral assays in Table 1, have a Thr residue at position 283; in other HIV-1 strains, Asn is common, and Val and Ile are also found. Thus, opportunities for side-chain hydrogen bonding exist in around 75% of natural HIV-1 strains. Thr 283 is in the LD loop of gp120, at the periphery of the CD4 interaction with gp120.6,12 Introduction of this new hydrogen-bonding interaction would be expected to improve the binding to gp120 and thus to enhance antiviral potency; however, the conformational heterogeneity observed for 10j would likely diminish the effect. Further development of pyrrolidine-substituted compounds may strengthen the interaction with this gp120 region through full engagement.

Compared to the 2-substituted pyrrolidine 10j, the structure of the 10h-gp120 coree complex demonstrated a different binding mode, with all four copies assuming the same conformation (Figures 4D and S3). Based on the structure of 10h, we note that the primary amine of the 3-aminopyrrolidine is positioned away from the protein surface and toward the solvent, similar to the pose assumed by conformer B of 10j. It is possible that the primary amine, being remote from any plausible interactions that might direct it toward the gp120 surface, would have enough conformational flexibility to direct the hydrophilic substituent away from the protein surface and toward the solvent. We therefore postulate that ligands with hydrophilic C(3) substitutions of the pyrrolidine ring may not contribute to the overall binding with gp120 due to solvation of the substituent, and therefore result in an equipotent compound compared with BNM-III-170. This hypothesis is consistent with the observed viral inhibition of analogues containing substitutions at the 3-position of the pyrrolidine ring (Table 1, 10e–h; BNM-III-170: IC50 HIV-1JRFL: 9.6 ± 2.9 μM).

In addition to the direct interactions made from the CD4mc ligands to gp120 in these crystal structures, we also observed water-mediated contacts from the methylguanidinium group on Indane position 2 to the side chain of Asn 425 (Figure 4F). Asn 425 has an additional hydrogen bond to Glu 370, with the water molecule also approaching Asp 368. Both Asp 368 and Glu 370 are always conserved among HIV strains and are essential for CD4 binding.20 These interactions suggest opportunities for further CD4mc development.

In summary, the results of this SAR study of our lead CD4mc BNM-III-170 reveal multiple avenues forward, with regard to potency improvement, sensitization of HIV-1-infected cells to ADCC responses, and tolerable substituent replacements of our lead CD4mc. Additionally, nondeleterious modifications of the 5-position Indane side chain may allow for future modulation of the pharmacokinetic properties of our CD4mc. More notably, we have discovered a novel interaction between gp120 residue Thr 283 and analogue 10j. In the future, guided by these structural data and computational modeling, we will seek to optimize interactions of the CD4mc with gp120 elements near Thr 283. We hypothesize that by continuing to explore this region, it may be possible to generate an increase in potency required for further CD4mc development and optimization.

Acknowledgments

We thank Irwin Chaiken and all the members of the P01 Consortium Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry. Dr. Charles Ross, and Dr. Jun Gu (University of Pennsylvania) are also acknowledged for their assistance obtaining mass and NMR spectra, respectively. Instrumentation supported by the NSF Major Research Instrumentation Program (award NSF CHE-1827457) and Vagelos Institute for Energy Science and Technology used in this study.

Glossary

Abbreviations

HIV-1

human immunodeficiency virus type 1

A-MLV

amphotropic murine leukemia virus

Env

HIV-1 viral envelope

CD4mc

CD4 mimetic compound

Na(OAc)3BH

sodium triacetoxyborohydride

Boc

tert-butoxycarbonyl

EtOH

ethanol

DCM

dichloromethane

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00376.

  • Synthesis, experimental methods and crystallographic data (PDF)

Accession Codes

Accession Codes Coordinates and structure factors have been deposited in the Protein Data Bank with the following accession codes: 7TJP (10j, CJF-II-195), 7TJO (10h, CJF-II-197-S)

Author Present Address

□ LG Chem., 30, MagokJungang 10-ro, Gangseo-gu, Seoul, South Korea

Author Contributions

▲ C.C. and C.J.F. contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This study was supported in part by NIH grant AI1 50471.

The authors declare no competing financial interest.

Supplementary Material

ml2c00376_si_001.pdf (863.2KB, pdf)

References

  1. United Nations , UNAIDS Fact Sheet 2021. 2021.
  2. WHO . HIV/AIDS: Data and Statistics.
  3. Abdool Karim Q.; Abdool Karim S. S.; Frohlich J. A.; Grobler A. C.; Baxter C.; Mansoor L. E.; Kharsany A. B. M.; Sibeko S.; Mlisana K. P.; Omar Z.; Gengiah T. N.; Maarschalk S.; Arulappan N.; Mlotshwa M.; Morris L.; Taylor D. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science 2010, 329, 1168–1174. 10.1126/science.1193748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clercq E. D. The design of drugs for HIV and HCV. Nat. Rev. Drug Disc. 2007, 6, 1001–1018. 10.1038/nrd2424. [DOI] [PubMed] [Google Scholar]
  5. Celum C.; Baeten J. M. Tenofovir-based pre-exposure prophylaxis for HIV prevention: evolving evidence. Curr. Op. Inf. Dis. 2012, 25, 51–57. 10.1097/QCO.0b013e32834ef5ef. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kwong P. D.; Wyatt R.; Robinson J.; Sweet R. W.; Sodroski J.; Hendrickson W. A. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998, 393, 648–659. 10.1038/31405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Wyatt R.; Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 1998, 280, 1884–1888. 10.1126/science.280.5371.1884. [DOI] [PubMed] [Google Scholar]
  8. Wilen C. B.; Tilton J. C.; Doms R. W. HIV: Cell Binding and Entry. Csh Perspect. Med. 2012, 2, a006866 10.1101/cshperspect.a006866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Melillo B.; Liang S.; Park J.; Schön A.; Courter J. R.; LaLonde J. M.; Wendler D. J.; Princiotto A. M.; Seaman M. S.; Freire E.; Sodroski J.; Madani N.; Hendrickson W. A.; Smith A. B. III Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition. ACS Med. Chem. Lett. 2016, 7, 330–334. 10.1021/acsmedchemlett.5b00471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Zhao Q.; Ma L.; Jiang S.; Lu H.; Liu S.; He Y.; Strick N.; Neamati N.; Debnath A. K. Identification of N-phenyl-N’-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4. Virology 2005, 339, 213–225. 10.1016/j.virol.2005.06.008. [DOI] [PubMed] [Google Scholar]
  11. Courter J. R.; Madani N.; Sodroski J.; Schön A.; Freire E.; Kwong P. D.; Hendrickson W. A.; Chaiken I. M.; LaLonde J. M.; Smith A. B. III Structure-Based Design, Synthesis and Validation of CD4-Mimetic Small Molecule Inhibitors of HIV-1 Entry: Conversion of a Viral Entry Agonist to an Antagonist. Acc. Chem. Res. 2014, 47, 1228–1237. 10.1021/ar4002735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Liu Y.; Schön A.; Freire E. Optimization of CD4/gp120 Inhibitors by Thermodynamic-Guided Alanine-Scanning Mutagenesis. Chem. Biol. Drug Des. 2013, 81, 72–78. 10.1111/cbdd.12075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chen J.; Park J.; Kirk S. M.; Chen H.-C.; Li X.; Lippincott D. J.; Melillo B.; Smith A. B. III Development of an Effective Scalable Enantioselective Synthesis of the HIV-1 Entry Inhibitor BNM-III-170 as the Bis-trifluoroacetate Salt. Org. Process Res. Dev. 2019, 23, 2464–2469. 10.1021/acs.oprd.9b00353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Princiotto A. M.; Vrbanac V. D.; Melillo B.; Park J.; Tager A. M.; Smith A. B. III; Sodroski J.; Madani N. A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection. J. Infect. Dis. 2018, 218, 471–475. 10.1093/infdis/jiy174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Madani N.; Princiotto A. M.; Mach L.; Ding S.; Prevost J.; Richard J.; Hora B.; Sutherland L.; Zhao C. A.; Conn B. P.; Bradley T.; Moody M. A.; Melillo B.; Finzi A.; Haynes B. F.; Smith A. B. III; Santra S.; Sodroski J. A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nat. Commun. 2018, 9, 2363. 10.1038/s41467-018-04758-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Friesner R. A.; Murphy R. B.; Repasky M. P.; Frye L. L.; Greenwood J. R.; Halgren T. A.; Sanschagrin P. C.; Mainz D. T. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein–Ligand Complexes. J. Med. Chem. 2006, 49, 6177–6196. 10.1021/jm051256o. [DOI] [PubMed] [Google Scholar]
  17. Richard J.; Veillette M.; Brassard N.; Iyer S. S.; Roger M.; Martin L.; Pazgier M.; Schön A.; Freire E.; Routy J.-P.; Smith A. B. III; Park J.; Jones D. M.; Courter J. R.; Melillo B. N.; Kaufmann D. E.; Hahn B. H.; Permar S. R.; Haynes B. F.; Madani N.; Sodroski J. G.; Finzi A. CD4 mimetics sensitize HIV-1-infected cells to ADCC. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (20), e2687–94. 10.1073/pnas.1506755112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Prevost J.; Tolbert W. D.; Medjahed H.; Sherburn R. T.; Madani N.; Zoubchenok D.; Gendron-Lepage G.; Gaffney A. E.; Grenier M. C.; Kirk S.; Vergara N.; Han C.; Mann B. T.; Chenine A. L.; Ahmed A.; Chaiken I.; Kirchhoff F.; Hahn B. H.; Haim H.; Abrams C. F.; Smith A. B.; Sodroski J.; Pazgier M.; Finzi A. The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site. mBio 2020, 11 (3), e00280–20. 10.1128/mBio.00280-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fritschi C. J.; Liang S.; Mohammadi M.; Anang S.; Moraca F.; Chen J.; Madani N.; Sodroski J. G.; Abrams C. F.; Hendrickson W. A.; Smith A. B. III Identification of gp120 residue His105 as a novel target for HIV-1 neutralization by small-molecule CD4-mimics. ACS Med. Chem. Lett. 2021, 12, 1824–1831. 10.1021/acsmedchemlett.1c00437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Olshevsky U.; Helseth E.; Furman C.; Li J.; Haseltine W.; Sodroski J. Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding. J. Virol. 1990, 64, 5701–5707. 10.1128/jvi.64.12.5701-5707.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml2c00376_si_001.pdf (863.2KB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES