Skip to main content

Advertisement

SpringerLink
Log in

Novel PCU cage diol peptides as potential targets against wild-type CSA HIV-1 protease: synthesis, biological screening and molecular modelling studies

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

We have synthesized a series of novel pentacycloundecane cage diol diacid (PCU diol diacid) incorporated C 2-symmetric peptides. Their activity against the resistance-prone wild-type C-South African (C-SA) HIV protease (HIV PR) is reported. These compounds were obtained in moderate yields of 42–72 %. Amongst the nine compounds reported herein only compound 6, 7, 10 and 11 showed moderate IC50 values of 5–10 μM. Peptides 7 and 10 contain two phenylglycine and two tryptophan amino acids, respectively as side arms to the cage diol. Phenylglycine is a non-natural amino acid. Docking and molecular dynamics (MD) studies were carried out to understand the binding mode of the PCU moiety at the active site of the HIV PR enzyme. The computational results show that the cage diol peptide fits quite comfortably inside the active site of the enzyme. Not much movement is observed during the MD simulation and the hydrogen bonds that develop between the inhibitor and the enzyme pocket suggest that the inhibitor/HIV PR complex is stable at room temperature.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Scheme 1
Scheme 2
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Avogadro (2010) An open-source molecular builder and visualization tool. Version 1.0.0. http://avogadro.Openmolecules.Net/

  • Baker WR, Condon SL (1993) Dipeptide isosteres. 1. Synthesis of dihydroxyethylene dipeptide isosteres via diastereoselective additions of alkyllithium reagents to n,n-dimethylhydrazones—preparation of renin and hiv-1 protease inhibitor transition-state mimics. J Org Chem 58(12):3277–3284

    Article  CAS  Google Scholar 

  • Barrè-Sinousi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axlerblin C, Vezinetbrun F, Rouzioux C, Rozenbaum W, Montagnier L (1983) Isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune-deficiency syndrome (aids). Science 220(4599):868–871

    Article  Google Scholar 

  • Berendsen HJC, Postma JPM, Vangunsteren WF, Dinola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81(8):3684–3690

    Article  CAS  Google Scholar 

  • Boyle GA, Govender T, Karpoormath R, Kruger HG (2007) Exo-8,exo-11-diallylpentacyclo[5.4.0.02,6.03,10.05,9]undecane-endo-8,endo-11-diol. Acta Crystallogr Sect E Struct Rep Online E63(12):o4797, o4797/1–o4797/22

    Google Scholar 

  • Boyle GA, Govender T, Karpoormath R, Kruger HG (2007) Exo-8,exo-11-divinylpentacyclo[5.4.0.02,6.03,10.05,6]undecane-endo-8,endo-11-diol. Acta Crystallogr Sect E Struct Rep Online E63(10):o3977, So3977/1–So3977/8

    Google Scholar 

  • Brik A, Wong CH (2003) Hiv-1 protease: mechanism and drug discovery. Org Biomol Chem 1(1):5–14

    Article  PubMed  CAS  Google Scholar 

  • Brookes KB, Hickmott PW, Jutle KK, Schreyer CA (1992) Introduction of pharmacophoric groups into polycyclic systems.4. Aziridine, oxiran, and tertiary beta-hydroxyethylamine derivatives of adamantane. South African J Chem 45(1):8–11

    CAS  Google Scholar 

  • Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA (1998) A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving hiv protease inhibitors. AIDS 12(7):F51–F58

    Article  PubMed  CAS  Google Scholar 

  • Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Feng Y, Xu Z, Ye T (2005) The total synthesis and reassignment of stereochemistry of dragonamide. Tetrahedron 61(47):11132–11140

    Article  CAS  Google Scholar 

  • Clavel F, Guetard D, Brunvezinet F, Chamaret S, Rey MA, Santosferreira MO, Laurent AG, Dauguet C, Katlama C, Rouzioux C, Klatzmann D, Champalimaud JL, Montagnier L (1986) Isolation of a new human retrovirus from west-African patients with aids. Science 233(4761):343–346

    Article  PubMed  CAS  Google Scholar 

  • Clemente JC, Coman RM, Thiaville MM, Janka LK, Jeung JA, Nukoolkarn S, Govindasamy L, Agbandje-McKenna M, McKenna R, Leelamanit W, Goodenow MM, Dunn BM (2006) Analysis of hiv-1crf_01 a/e protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir. Biochemistry 45(17):5468–5477

    Article  PubMed  CAS  Google Scholar 

  • Cookson RC, Crundwell E, Hill RR, Hudec J (1964) Photochemical cyclisation of diels–alder adducts. J Chem Soc (Resumed) 3062–3075

  • Desolms SJ, Giuliani EA, Guare JP, Vacca JP, Sanders WM, Graham SL, Wiggins JM, Darke PL, Sigal IS, Zugay JA, Emini EA, Schleif WA, Quintero JC, Anderson PS, Huff JR (1991) Design and synthesis of hiv protease inhibitors—variations of the carboxy terminus of the hiv protease inhibitor-l-682,679. J Med Chem 34(9):2852–2857

    Article  PubMed  CAS  Google Scholar 

  • Doyon L, Tremblay S, Bourgon L, Wardrop E, Cordingley MG (2005) Selection and characterization of hiv-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antiviral Res 68(1):27–35

    Article  PubMed  CAS  Google Scholar 

  • Duan Y, Wu C, Chowdhury S, Lee MC, Xiong GM, Zhang W, Yang R, Cieplak P, Luo R, Lee T, Caldwell J, Wang JM, Kollman PA (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24:1999–2012

    Article  PubMed  CAS  Google Scholar 

  • Erickson JW, Burt SK (1996) Structural mechanisms of hiv drug resistance. Annu Rev Pharmacol Toxicol 36:545–571

    Article  PubMed  CAS  Google Scholar 

  • Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103(19):8577–8593

    Article  CAS  Google Scholar 

  • Flexner C (1998) Hiv-protease inhibitors. N Engl J Med 338(18):1281–1292

    Article  PubMed  CAS  Google Scholar 

  • Freed EO (1998) Hiv-1 gag proteins: diverse functions in the virus life cycle. Virology 251(1):1–15

    Article  PubMed  CAS  Google Scholar 

  • Frimurer TM, Peters GH, Iversen LF, Andersen HS, Moller NPH, Olsen OH (2003) Ligand-induced conformational changes: improved predictions of ligand binding conformations and affinities. Biophys J 84(4):2273–2281

    Article  PubMed  CAS  Google Scholar 

  • Gallo RC, Sarin PS, Gelmann EP, Robertguroff M, Richardson E, Kalyanaraman VS, Mann D, Sidhu GD, Stahl RE, Zollapazner S, Leibowitch J, Popovic M (1983) Isolation of human t-cell leukemia-virus in acquired immune-deficiency syndrome (aids). Science 220(4599):865–867

    Article  PubMed  CAS  Google Scholar 

  • Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan M, Haynes BF, Palker TJ, Redfield R, Oleske J, Safai B, White G, Foster P, Markham PD (1984) Frequent detection and isolation of cytopathic retroviruses (htlv-iii) from patients with aids and at risk for aids. Science 224(4648):500–503

    Article  PubMed  CAS  Google Scholar 

  • Geldenhuys WJ, Malan SF, Bloomquist JR, Marchand AP, Van der Schyf CJ (2005) Pharmacology and structure–activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives. Med Res Rev 25(1):21–48

    Article  PubMed  CAS  Google Scholar 

  • Gerzon K, Kau D (1967) The adamantyl group in medicinal agents. 3. Nucleoside 5′-adamantoates. The adamantoyl function as a protecting group. J Med Chem 10(2):189–199

    Article  PubMed  CAS  Google Scholar 

  • Gerzon K, Tobias DJ Sr, Holmes RE, Rathbun RE, Kattau RW (1967) The adamantyl group in medicinal agents. IV. Sedative action of 3,5,7-trimethyladamantane-1-carboxamide and related agents. J Med Chem 10(4):603–606

    Article  PubMed  CAS  Google Scholar 

  • Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1(1):55–68

    Article  PubMed  CAS  Google Scholar 

  • Ghosh AK, Dawson ZL, Mitsuya H (2007) Darunavir, a conceptually new hiv-1 protease inhibitor for the treatment of drug-resistant hiv. Bioorg Med Chem 15(24):7576–7580

    Article  PubMed  CAS  Google Scholar 

  • Govender T, Hariprakasha HK, Kruger HG, Marchand AP (2003) Synthesis and transport studies of a new class of cage-annulated chiral macrocycles. Tetrahedron Asymmetry 14(11):1553–1557

    Article  CAS  Google Scholar 

  • Grobler E, Grobler A, Van der Schyf CJ, Malan SF (2006) Effect of polycyclic cage amines on the transmembrane potential of neuronal cells. Bioorg Med Chem 14(4):1176–1181

    Article  PubMed  CAS  Google Scholar 

  • Gutierrez OA, Salas E, Hernandez Y, Lissi EA, Castrillo G, Reyes O, Garay H, Aguilar A, Garcia B, Otero A, Chavez MA, Duarte CA (2002) An immunoenzymatic solid-phase assay for quantitative determination of hiv-1 protease activity. Anal Biochem 307(1):18–24

    Article  PubMed  CAS  Google Scholar 

  • Hodge CN, Aldrich PE, Bacheler LT, Chang CH, Eyermann CJ, Garber S, Grubb M, Jackson DA, Jadhav PK, Korant B, Lam PY, Maurin MB, Meek JL, Otto MJ, Rayner MM, Reid C, Sharpe TR, Shum L, Winslow DL, Erickson-Viitanen S (1996) Improved cyclic urea inhibitors of the hiv-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and x-ray crystal structure of dmp 450. Chem Biol 3(4):301–314

    Article  PubMed  CAS  Google Scholar 

  • Holmes CP, Jones DG (1995) Reagents for combinatorial organic synthesis: development of a new o-nitrobenzyl photolabile linker for solid phase synthesis. J Org Chem 60(8):2318–2319

    Article  CAS  Google Scholar 

  • Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28(6):1145–1152

    Article  PubMed  CAS  Google Scholar 

  • Huff JR (1991) Hiv protease—a novel chemotherapeutic target for aids. J Med Chem 34(8):2305–2314

    Article  PubMed  CAS  Google Scholar 

  • Ito FM, Petroni JM, de Lima DP, Beatriz A, Marques MR, de Moraes MO, Costa-Lotufo LV, Montnegro RC, Magalhaes HIF, Pessoa CDO (2007) Synthesis and biological evaluation of rigid polycyclic derivatives of the diels-alder adduct tricyclo[6.2.1.0(2,7)]undeca-4-9-dien-3,6-dione. Molecules 12(2):271–282

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  • Joubert J, Geldenhuys WJ, Van der Schyf CJ, Oliver DW, Kruger HG, Govender T, Malan SF (2012) Polycyclic cage structures as lipophilic scaffolds for neuroactive drugs. ChemMedChem 7(3):375–384

    Article  PubMed  CAS  Google Scholar 

  • Kaldor SW, Kalish VJ, Davies JF 2nd, Shetty BV, Fritz JE, Appelt K, Burgess JA, Campanale KM, Chirgadze NY, Clawson DK, Dressman BA, Hatch SD, Khalil DA, Kosa MB, Lubbehusen PP, Muesing MA, Patick AK, Reich SH, Su KS, Tatlock JH (1997) Viracept (nelfinavir mesylate, ag1343): a potent, orally bioavailable inhibitor of hiv-1 protease. J Med Chem 40(24):3979–3985

    Article  PubMed  CAS  Google Scholar 

  • Kaltenbach RF 3rd, Nugiel DA, Lam PY, Klabe RM, Seitz SP (1998) Stereoisomers of cyclic urea hiv-1 protease inhibitors: synthesis and binding affinities. J Med Chem 41(25):5113–5117

    Article  PubMed  CAS  Google Scholar 

  • Karpoormath R, Govender P, Kruger HG, Govender T, Maguire GEM (2010) N, n’-[(8-endo,11-endo-dihydroxypentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-diyl)bis(methylenecarbonyl)]di-l-phenylalanine. Acta Crystallogr Sect E Struct Rep Online 66(10):o2537–o2538

    Article  PubMed  CAS  Google Scholar 

  • Karpoormath R, Sayed Y, Govender P, Govender T, Kruger HG, Soliman MES, Maguire GEM (2011) Pentacycloundecane derived hydroxy acid peptides: a new class of irreversible non-scissile ether bridged type isoster as potential hiv-1 wild type c-sa protease inhibitors. Bioorg Chem 40(1):19–29. doi:10.1016/j.bioorg.2011.08.002

    PubMed  Google Scholar 

  • Kempf DJ, Marsh KC, Denissen JF, McDonald E, Vasavanonda S, Flentge CA, Green BE, Fino L, Park CH, Kong XP, Wideburg NE, Saldivar A, Ruiz L, Kati WM, Sham HL, Robins T, Stewart KD, Hsu A, Plattner JJ, Leonard JM, Norbeck DW (1995) Abt-538 is a potent inhibitor of human-immunodeficiency-virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci USA 92(7):2484–2488

    Article  PubMed  CAS  Google Scholar 

  • Kim EE, Baker CT, Dwyer MD, Murcko MA, Rao BG, Tung RD, Navia MA (1995) Crystal-structure of hiv-1 protease in complex with vx-478, a potent and orally bioavailable inhibitor of the enzyme. J Am Chem Soc 117(3):1181–1182

    Article  CAS  Google Scholar 

  • Lassiani L, Pavan MV, Berti F, Kokotos G, Markidis T, Mennuni L, Makovec F, Varnavas A (2009) Anthranilic acid based cck1 receptor antagonists: blocking the receptor with the same ‘words’ of the endogenous ligand. Bioorg Med Chem 17(6):2336–2350

    Article  PubMed  CAS  Google Scholar 

  • Lee T, Laco GS, Torbett BE, Fox HS, Lerner DL, Elder JH, Wong CH (1998) Analysis of the s3 and s3′ subsite specificities of feline immunodeficiency virus (fiv) protease: development of a broad-based protease inhibitor efficacious against fiv, siv, and hiv in vitro and ex vivo. Proc Natl Acad Sci U S A 95(3):939–944

    Article  PubMed  CAS  Google Scholar 

  • Levitskaia TG, Moyer BA, Bonnesen PV, Marchand AP, Krishnudu K, Chen ZB, Huang ZL, Kruger HG, McKim AS (2001) Novel approach to sodium hydroxide separation: synergistic pseudo-hydroxide extraction by a fluorinated alcohol and cage-functionalized crown ethers. J Am Chem Soc 123(48):12099–12100

    Article  PubMed  CAS  Google Scholar 

  • Levy JA, Hoffman AD, Kramer SM, Landis JA, Shimabukuro JM (1984) Isolation of lymphocytopathic retroviruses from san-francisco patients with aids. Science 225(4664):840–842

    Article  PubMed  CAS  Google Scholar 

  • Li YG, Zhang J, Xu WF, Zhu HW, Li X (2010) Novel matrix metalloproteinase inhibitors derived from quinoxalinone scaffold (part i). Bioorg Med Chem 18(4):1516–1525

    Article  PubMed  CAS  Google Scholar 

  • Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M (1998) “Buffalo hump” in men with hiv-1 infection. Lancet 351(9106):867–870

    Article  PubMed  CAS  Google Scholar 

  • Locuson CW, Gannett PM, Ayscue R, Tracy TS (2007) Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome p4502c9. J Med Chem 50(6):1158–1165

    Article  PubMed  CAS  Google Scholar 

  • Makatini MM, Petzold K, Sriharsha SN, Ndlovu N, Soliman MES, Honarparvar B, Parboosing R, Naidoo A, Arvidsson PI, Sayed Y, Govender P, Maguire GEM, Kruger HG, Govender T (2011a) Synthesis and structural studies of pentacycloundecane-based hiv-1 pr inhibitors: a hybrid 2d nmr and docking/qm/mm/md approach. Eur J Med Chem 46(9):3976–3985

    Article  PubMed  CAS  Google Scholar 

  • Makatini MM, Petzold K, Sriharsha SN, Soliman MES, Honarparvar B, Arvidsson PI, Sayed Y, Govender P, Maguire GEM, Kruger HG, Govender T (2011b) Pentacycloundecane-based inhibitors of wild-type c-south african hiv-protease. Bioorg Med Chem Lett 21(8):2274–2277

    Article  PubMed  CAS  Google Scholar 

  • Marchand AP, Allen RW (1974) Improved synthesis of pentacyclo[5.4.0.02,6.03,10.05,9]undecane. J Org Chem 39(11):1596–1597

    Article  CAS  Google Scholar 

  • Martinez E, Casamitjana R, Conget I, Gatell JM (1998) Protease inhibitor-associated hyperinsulinaemia. Aids 12(15):2077–2079

    Article  PubMed  CAS  Google Scholar 

  • Mastrolorenzo A, Rusconi S, Scozzafava A, Barbaro G, Supuran CT (2007) Inhibitors of hiv-1 protease: current state of the art 10 years after their introduction. From antiretroviral drugs to antifungal, antibacterial and antitumor agents based on aspartic protease inhibitors. Curr Med Chem 14(26):2734–2748

    Article  PubMed  CAS  Google Scholar 

  • Meek TD (1992) Inhibitors of hiv-1 protease. J Enzyme Inhib 6(1):65–98

    Article  PubMed  CAS  Google Scholar 

  • Meek TD, Lambert DM, Metcalf BW, Petteway SR, Dreyer GB (1990) Hiv-1 protease inhibitors. In: Clereq ED (ed) Design of anti-aids drugs. Elservier, Amsterdam, pp 225–265

    Google Scholar 

  • Miller SM, Simon RJ, Ng S, Zuckermann RN, Kerr JM, Moos WH (1994) Proteolytic studies of homologous peptide and n-substituted glycine peptoid oligomers. Bioorg Med Chem Lett 4(22):2657–2662

    Article  CAS  Google Scholar 

  • Miller SM, Simon RJ, Ng S, Zuckermann RN, Kerr JM, Moos WH (1995) Comparison of the proteolytic susceptibilities of homologous l-amino acid, d-amino acid, and n-substituted glycine peptide and peptoid oligomers. Drug Dev Res 35(1):20–32

    Article  CAS  Google Scholar 

  • Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J (1998) Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 351(9106):871–875

    Article  PubMed  CAS  Google Scholar 

  • Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19(14):1639–1662

    Article  CAS  Google Scholar 

  • Mosebi S, Morris L, Dirr HW, Sayed Y (2008) Active-site mutations in the south african human immunodeficiency virus type 1 subtype c protease have a significant impact on clinical inhibitor binding: kinetic and thermodynamic study. J Virol 82(22):11476–11479

    Article  PubMed  CAS  Google Scholar 

  • Oliver DW, Dekker TG, Snyckers FO, Fourie TG (1991) Synthesis and biological activity of d3-trishomocubyl-4-amines. J Med Chem 34(2):851–854

    Article  PubMed  CAS  Google Scholar 

  • Onajole OK, Govender K, Govender P, van Helden PD, Kruger HG, Maguire GEM, Muthusamy K, Pillay M, Wiid I, Govender T (2009) Pentacycloundecane-derived cyclic tetra-amines: synthesis and evaluation as potent anti-tuberculosis agents. Eur J Med Chem 44(11):4297–4305

    Article  PubMed  CAS  Google Scholar 

  • Onajole OK, Govender P, van Helden PD, Kruger HG, Maguire GEM, Wiid I, Govender T (2010a) Synthesis and evaluation of sq109 analogues as potential anti-tuberculosis candidates. Eur J Med Chem 45(5):2075–2079

    Article  PubMed  CAS  Google Scholar 

  • Onajole OK, Makatini MM, Govender P, Govender T, Maguire GEM, Kruger HG (2010b) Synthesis and nmr assignment of pentacycloundecane precursors of potential pharmaceutical agents. Magn Reson Chem 48(3):249–255

    PubMed  CAS  Google Scholar 

  • Pecanha EP, Figueiredo LJO, Brindeiro RM, Tanuri A, Calazans AR, Antunes OAC (2003) Synthesis and anti-hiv activity of new c2 symmetric derivatives designed as hiv-1 protease inhibitors. Farmaco 58(2):149–157

    Article  PubMed  CAS  Google Scholar 

  • Reetz MT, Merk C, Mehler G (1998) Preparation of novel hiv-protease inhibitors. Chem Commun 19:2075–2076

    Article  Google Scholar 

  • Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Krohn A, Lambert RW, Merrett JH, Mills JS, Parkes KEB, Redshaw S, Ritchie AJ, Taylor DL, Thomas GJ, Machin PJ (1990) Rational design of peptide-based hiv proteinase-inhibitors. Science 248(4953):358–361

    Article  PubMed  CAS  Google Scholar 

  • Robinson BS, Riccardi KA, Gong YF, Guo Q, Stock DA, Blair WS, Terry BJ, Deminie CA, Djang F, Colonno RJ, Lin PF (2000) Bms-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents. Antimicrob Agents Chemother 44(8):2093–2099

    Article  PubMed  CAS  Google Scholar 

  • Rutjes FPJT, Veerman JJN, Meester WJN, Hiemstra H, Schoemaker HE (1999) Synthesis of enantiopure functionalized pipecolic acids via amino acid derived n-acyliminium ions. Eur J Org Chem 5:1127–1135

    Article  Google Scholar 

  • Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints—molecular dynamics of n-alkanes. J Comput Phys 23(3):327–341

    Article  CAS  Google Scholar 

  • Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17(1):57–61

    PubMed  CAS  Google Scholar 

  • Santagada V, Fiorino F, Perissutti E, Severino B, De Filippis V, Vivenzio B, Caliendo G (2001) Microwave-enhanced solution coupling of the î±, î±-dialkyl amino acid, aib. Tetrahedron Lett 42(31):5171–5173

    Article  CAS  Google Scholar 

  • Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen XQ, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM, Plattner JJ, Norbeck DW (1998) Abt-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 42(12):3218–3224

    PubMed  CAS  Google Scholar 

  • Simon RJ, Kania RS, Zuckermann RN, Huebner VD, Jewell DA, Banville S, Ng S, Wang L, Rosenberg S, Marlowe CK, Spellmeyer DC, Tan RY, Frankel AD, Santi DV, Cohen FE, Bartlett PA (1992) Peptoids—a modular approach to drug discovery. Proc Natl Acad Sci U S A 89(20):9367–9371

    Article  PubMed  CAS  Google Scholar 

  • Soares TA, Goodsell DS, Ferreira R, Olson AJ, Briggs JM (2000) Ionization state and molecular docking studies for the macrophage migration inhibitory factor: the role of lysine 32 in the catalytic mechanism. J Mol Recognit 13(3):146–156

    Article  PubMed  CAS  Google Scholar 

  • Stamatiou G, Kolocouris A, Kolocouris N, Fytas G, Foscolos GB, Neyts J, De Clercq E (2001) Novel 3-(2-adamantyl)pyrrolidines with potent activity against influenza a virus-identification of aminoadamantane derivatives bearing two pharmacophoric amine groups. Bioorg Med Chem Lett 11(16):2137–2142

    Article  PubMed  CAS  Google Scholar 

  • Turner BG, Summers MF (1999) Structural biology of hiv. J Mol Biol 285(1):1–32

    Article  PubMed  CAS  Google Scholar 

  • UNAIDS/WHO (2010) UNAIDS report on the global aids epidemic. In UNAIDS, UNAIDS, Geneva

  • Vacca JP, Dorsey BD, Schleif WA, Levin RB, Mcdaniel SL, Darke PL, Zugay J, Quintero JC, Blahy OM, Roth E, Sardana VV, Schlabach AJ, Graham PI, Condra JH, Gotlib L, Holloway MK, Lin J, Chen IW, Vastag K, Ostovic D, Anderson PS, Emini EA, Huff JR (1994) L-735,524—an orally bioavailable human-immunodeficiency-virus type-1 protease inhibitor. Proc Natl Acad Sci USA 91(9):4096–4100

    Article  PubMed  CAS  Google Scholar 

  • Viraben R, Aquilina C (1998) Indinavir-associated lipodystrophy. Aids 12(6):F37–F39

    Article  PubMed  CAS  Google Scholar 

  • Wallace AC, Laskowski RA, Thornton JM (1995) Ligplot—a program to generate schematic diagrams of protein ligand interactions. Protein Eng 8(2):127–134

    Article  PubMed  CAS  Google Scholar 

  • Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, Bogner JR, Landgraf R, Goebel FD (1998) Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in hiv-1-infected patients. Aids 12(15):F167–F173

    Article  PubMed  CAS  Google Scholar 

  • Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174

    Article  PubMed  CAS  Google Scholar 

  • Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2005) Development and testing of a general amber force field (vol 25, pg 1157, 2004). J Comput Chem 26(1):114–115

    Article  CAS  Google Scholar 

  • Wang JM, Wang W, Kollman PA, Case DA (2006) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graph Model 25(2):247–260

    Article  PubMed  Google Scholar 

  • Waters L, Nelson M (2007a) Long-term complications of antiretroviral therapy: lipoatrophy. Int J Clin Pract 61(6):999–1014

    Article  PubMed  CAS  Google Scholar 

  • Waters L, Nelson M (2007b) Why do patients fail hiv therapy? Int J Clin Pract 61(6):983–990

    Article  PubMed  CAS  Google Scholar 

  • Wlodawer A (2002) Rational approach to aids drug design through structural biology. Annu Rev Med 53:595–614

    Article  PubMed  CAS  Google Scholar 

  • Wlodawer A, Vondrasek J (1998) Inhibitors of hiv-1 protease: a major success of structure-assisted drug design. Annu Rev Biophys Biomol Struct 27:249–284

    Article  PubMed  CAS  Google Scholar 

  • Zah J, Terre’Blanche G, Erasmus E, Malan SF (2003) Physicochemical prediction of a brain–blood distribution profile in polycyclic amines. Bioorg Med Chem 11(17):3569–3578

    Article  PubMed  CAS  Google Scholar 

  • Zuckermann RN, Kerr JM, Kent SBH, Moos WH (1992) Efficient method for the preparation of peptoids [oligo(n-substituted glycines)] by submonomer solid-phase synthesis. J Am Chem Soc 114(26):10646–10647

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by NRF (SA) TG (GUN: 66319), KP (GUN: 69728), HGK and PIA (SA-Sweden bilateral grant). We thank Aspen Pharmacare, University of KwaZulu-Natal and the NRF for financial support and the CHPC (http://www.chpc.ac.za) for computational resources. We also thank Prof. Fernando Albericio (University of Barcelona) for his advice with the synthesis of compound 13, Dr Patrick Govender for assistance with the HIV testing and Mr. Dilip Jagjivan (UKZN, South Africa) for his assistance with the NMR experiments.

Author information

Authors and Affiliations

  1. Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu Natal, Durban, 4001, South Africa

    Thavendran Govender, Hendrik G. Kruger & Glenn E. M. Maguire

  2. Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, 1 Jan Smuts Avenue, Johannesburg, 2050, South Africa

    Yasien Sayed

  3. School of Pharmacy and Pharmacology, University of KwaZulu Natal, Durban, 4001, South Africa

    Rajshekhar Karpoormath & Mahmoud E. S. Soliman

  4. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    Mahmoud E. S. Soliman

Authors
  1. Rajshekhar Karpoormath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasien Sayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thavendran Govender
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hendrik G. Kruger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahmoud E. S. Soliman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Glenn E. M. Maguire
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hendrik G. Kruger or Glenn E. M. Maguire.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2285 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karpoormath, R., Sayed, Y., Govender, T. et al. Novel PCU cage diol peptides as potential targets against wild-type CSA HIV-1 protease: synthesis, biological screening and molecular modelling studies. Med Chem Res 22, 3918–3933 (2013). https://doi.org/10.1007/s00044-012-0350-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-012-0350-1

Keywords

Search

Navigation