WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H555391
CAS#: 1352879-65-2
Description: PF-3450074, also known as PF74, is a HIV-1 inhibitor that targets HIV capsid protein. PF74 binds specifically to HIV-1 particles and triggers premature HIV-1 uncoating in target cells. PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex. PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating.
Hodoodo Cat#: H555391
Name: PF3450074
CAS#: 1352879-65-2
Chemical Formula: C27H27N3O2
Exact Mass: 425.21
Molecular Weight: 425.532
Elemental Analysis: C, 76.21; H, 6.40; N, 9.87; O, 7.52
Related CAS #: 1352879-65-2
Synonym: PF74; PF-74; PF 74; PF-3450074; PF 3450074; PF3450074;
IUPAC/Chemical Name: 2-Methyl-N-[(1S)-2-(methylphenylamino)-2-oxo-1-(phenylmethyl)ethyl]- 1H-indole-3-acetamide
InChi Key: ACDFWSNAQWFRRF-VWLOTQADSA-N
InChi Code: InChI=1S/C27H27N3O2/c1-19-23(22-15-9-10-16-24(22)28-19)18-26(31)29-25(17-20-11-5-3-6-12-20)27(32)30(2)21-13-7-4-8-14-21/h3-16,25,28H,17-18H2,1-2H3,(H,29,31)/t25-/m0/s1
SMILES Code: O=C(N[C@@H](CC1=CC=CC=C1)C(N(C)C2=CC=CC=C2)=O)CC3=C(C)NC4=C3C=CC=C4
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | PF-3450074 (PF-74) is a specifical inhibitor of HIV-1 capsid protein (CA) and displays a broad-spectrum inhibition of HIV isolates with submicromolar potency (EC50=8-640 nM). |
| In vitro activity: | It was assessed whether PF74 could additionally antagonize NUP153C engagement by CA in the context of HIV-1 infection, given the caveat that one could not unambiguously correlate data from protein binding assays with effects from PF74-induced capsid destabilization in cells. PF74 exhibited dose-dependent inhibition of WT HIV-1 and N74D CA mutant viral infection, but had no effect on CA mutant T54A/N57A, which lacks the critical Asn57 side-chain necessary for PF74 binding. WT virus was noticeably less sensitive to PF74 in Trim-NUP153C expressing cells, with an EC90 of 5.65 µM as opposed to 0.65 µM in control cells. The competing effect of PF74 on Trim-NUP153C inhibition seemingly occurred between the concentrations of 0.1 and 1 µM, as the inhibition curves within the two cell lines were nearly superimposable outside of these concentrations. N74D CA mutant virus also exhibited a shift in the PF74 EC90 concentration in Trim-NUP153C cells, though this occurred at higher PF74 concentrations than with the WT virus. Reference: PLoS Pathog. 2013;9(10):e1003693. https://pubmed.ncbi.nlm.nih.gov/24130490/ |
| In vivo activity: | The altered dependence of 4Mut and 5Mut infection on expression of TNPO3 and RanBP2 prompted examination of the fitness of 4Mut in primary targets of HIV-1 replication in vivo—i.e., CD4+ T cells and macrophages. Activated primary CD4+ T cells supported robust replication of wild-type X4- and R5-tropic HIV-1 (Fig. 9A). In contrast, and as observed with the CEM T cell line, 4Mut was markedly attenuated, as was 5Mut. Addition of PF74 or BI-2 promoted 4Mut replication in the cells. In macrophages, in contrast, replication of the 4Mut virus (rendered CCR5 dependent by replacement of the NL4-3 env by that of HIV-1.BaL) was severely impaired and was not stimulated by PF74 or BI-2. Surprisingly, replication of the N74D mutant, which we had included as a control, was markedly stimulated by PF74 and BI-2 in macrophages at drug concentrations that were only moderately inhibitory toward the wild-type virus. We conclude that the 4Mut virus, while exhibiting features of the N74D mutant in terms of host factor requirement, responds differently to capsid-targeting inhibitors in macrophages. Reference: J Virol. 2015 Sep;89(17):9068-79. https://pubmed.ncbi.nlm.nih.gov/26109731/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 250.0 | 587.52 |
The following data is based on the product molecular weight 425.53 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Matreyek KA, Yücel SS, Li X, Engelman A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 2013;9(10):e1003693. doi: 10.1371/journal.ppat.1003693. Epub 2013 Oct 10. PMID: 24130490; PMCID: PMC3795039. 2. Zhou J, Price AJ, Halambage UD, James LC, Aiken C. HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry. J Virol. 2015 Sep;89(17):9068-79. doi: 10.1128/JVI.00340-15. Epub 2015 Jun 24. PMID: 26109731; PMCID: PMC4524096. |
| In vitro protocol: | 1. Matreyek KA, Yücel SS, Li X, Engelman A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 2013;9(10):e1003693. doi: 10.1371/journal.ppat.1003693. Epub 2013 Oct 10. PMID: 24130490; PMCID: PMC3795039. 2. Zhou J, Price AJ, Halambage UD, James LC, Aiken C. HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry. J Virol. 2015 Sep;89(17):9068-79. doi: 10.1128/JVI.00340-15. Epub 2015 Jun 24. PMID: 26109731; PMCID: PMC4524096. |
| In vivo protocol: | 1. Zhou J, Price AJ, Halambage UD, James LC, Aiken C. HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry. J Virol. 2015 Sep;89(17):9068-79. doi: 10.1128/JVI.00340-15. Epub 2015 Jun 24. PMID: 26109731; PMCID: PMC4524096. |
1: Sowd GA, Shi J, Aiken C. HIV-1 CA inhibitors are antagonized by inositol phosphate stabilization of the viral capsid in cells. J Virol. 2021 Oct 6:JVI0144521. doi: 10.1128/JVI.01445-21. Epub ahead of print. PMID: 34613803.
2: Zhang X, Sun L, Meuser ME, Zalloum WA, Xu S, Huang T, Cherukupalli S, Jiang X, Ding X, Tao Y, Kang D, De Clercq E, Pannecouque C, Dick A, Cocklin S, Liu X, Zhan P. Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors. Eur J Med Chem. 2021 Sep 16;226:113848. doi: 10.1016/j.ejmech.2021.113848. Epub ahead of print. PMID: 34592608.
3: Li J, Jiang X, Dick A, Prakash Sharma P, Chen CH, Rathi B, Kang D, Wang Z, Ji X, Lee KH, Cocklin S, Liu X, Zhan P. Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors. Bioorg Med Chem. 2021 Oct 15;48:116414. doi: 10.1016/j.bmc.2021.116414. Epub 2021 Sep 17. PMID: 34562701.
4: Chia T, Nakamura T, Amano M, Takamune N, Matsuoka M, Nakata H. A Small Molecule, ACAi-028, with Anti-HIV-1 Activity Targets a Novel Hydrophobic Pocket on HIV-1 Capsid. Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0103921. doi: 10.1128/AAC.01039-21. Epub 2021 Jul 6. PMID: 34228546; PMCID: PMC8448090.
5: Ruddell S, Sugrue E, Memarzadeh S, Hellam LM, Wilson SJ, France DJ. Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74. Molecules. 2021 Jun 26;26(13):3919. doi: 10.3390/molecules26133919. PMID: 34206893; PMCID: PMC8272108.
6: Sun Q, Levy RM, Kirby KA, Wang Z, Sarafianos SG, Deng N. Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation. Viruses. 2021 May 15;13(5):920. doi: 10.3390/v13050920. PMID: 34063519; PMCID: PMC8156065.
7: Sahani RL, Diana-Rivero R, Vernekar SKV, Wang L, Du H, Zhang H, Castaner AE, Casey MC, Kirby KA, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Design, Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74. Viruses. 2021 Mar 15;13(3):479. doi: 10.3390/v13030479. PMID: 33804121; PMCID: PMC8000227.
8: Wang L, Casey MC, Vernekar SKV, Sahani RL, Kirby KA, Du H, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability. Acta Pharm Sin B. 2021 Mar;11(3):810-822. doi: 10.1016/j.apsb.2020.07.016. Epub 2020 Jul 31. PMID: 33777683; PMCID: PMC7982424.
9: Meuser ME, Reddy PAN, Dick A, Maurancy JM, Salvino JM, Cocklin S. Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow. J Med Chem. 2021 Apr 8;64(7):3747-3766. doi: 10.1021/acs.jmedchem.0c01810. Epub 2021 Mar 22. PMID: 33750123; PMCID: PMC8043142.
10: Jennings J, Shi J, Varadarajan J, Jamieson PJ, Aiken C. The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid. mBio. 2020 Dec 1;11(6):e02820-20. doi: 10.1128/mBio.02820-20. PMID: 33262260; PMCID: PMC7733946.
11: Twizerimana AP, Scheck R, Becker D, Zhang Z, Wammers M, Avelar L, Pflieger M, Häussinger D, Kurz T, Gohlke H, Münk C. Cell Type-Dependent Escape of Capsid Inhibitors by Simian Immunodeficiency Virus SIVcpz. J Virol. 2020 Nov 9;94(23):e01338-20. doi: 10.1128/JVI.01338-20. PMID: 32907979; PMCID: PMC7654278.
12: Sumner RP, Harrison L, Touizer E, Peacock TP, Spencer M, Zuliani-Alvarez L, Towers GJ. Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA. EMBO J. 2020 Oct 15;39(20):e103958. doi: 10.15252/embj.2019103958. Epub 2020 Aug 27. PMID: 32852081; PMCID: PMC7560218.
13: Wang L, Casey MC, Vernekar SKV, Sahani RL, Kankanala J, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Novel HIV-1 capsid-targeting small molecules of the PF74 binding site. Eur J Med Chem. 2020 Oct 15;204:112626. doi: 10.1016/j.ejmech.2020.112626. Epub 2020 Jul 19. PMID: 32814250; PMCID: PMC7530112.
14: Dharan A, Bachmann N, Talley S, Zwikelmaier V, Campbell EM. Nuclear pore blockade reveals that HIV-1 completes reverse transcription and uncoating in the nucleus. Nat Microbiol. 2020 Sep;5(9):1088-1095. doi: 10.1038/s41564-020-0735-8. Epub 2020 Jun 1. PMID: 32483230.
15: Wang L, Casey MC, Vernekar SKV, Do HT, Sahani RL, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Chemical profiling of HIV-1 capsid-targeting antiviral PF74. Eur J Med Chem. 2020 Aug 15;200:112427. doi: 10.1016/j.ejmech.2020.112427. Epub 2020 May 12. PMID: 32438252; PMCID: PMC7492092.
16: Dostálková A, Škach K, Kaufman F, Křížová I, Hadravová R, Flegel M, Ruml T, Hrabal R, Rumlová M. PF74 and Its Novel Derivatives Stabilize Hexameric Lattice of HIV-1 Mature-Like Particles. Molecules. 2020 Apr 20;25(8):1895. doi: 10.3390/molecules25081895. PMID: 32325987; PMCID: PMC7221806.
17: Vernekar SKV, Sahani RL, Casey MC, Kankanala J, Wang L, Kirby KA, Du H, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules. Viruses. 2020 Apr 16;12(4):452. doi: 10.3390/v12040452. PMID: 32316297; PMCID: PMC7232165.
18: Sun L, Dick A, Meuser ME, Huang T, Zalloum WA, Chen CH, Cherukupalli S, Xu S, Ding X, Gao P, Kang D, De Clercq E, Pannecouque C, Cocklin S, Lee KH, Liu X, Zhan P. Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities. J Med Chem. 2020 May 14;63(9):4790-4810. doi: 10.1021/acs.jmedchem.0c00015. Epub 2020 Apr 29. PMID: 32298111; PMCID: PMC8011991.
19: Jiang X, Wu G, Zalloum WA, Meuser ME, Dick A, Sun L, Chen CH, Kang D, Jing L, Jia R, Cocklin S, Lee KH, Liu X, Zhan P. Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors. RSC Adv. 2019;9(50):28961-28986. doi: 10.1039/c9ra05869a. Epub 2019 Sep 16. PMID: 32089839; PMCID: PMC7034945.
20: Sun L, Huang T, Dick A, Meuser ME, Zalloum WA, Chen CH, Ding X, Gao P, Cocklin S, Lee KH, Zhan P, Liu X. Design, synthesis and structure-activity relationships of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as novel HIV-1 capsid inhibitors with promising antiviral activities. Eur J Med Chem. 2020 Mar 15;190:112085. doi: 10.1016/j.ejmech.2020.112085. Epub 2020 Jan 24. PMID: 32066010; PMCID: PMC7053825.
