Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells
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1 Pro. Nati. Aad. Si. USA Vol. 91, pp , April 1994 Medial Sienes Triterpene derivatives that blok entry of human immunodefiieny virus type 1 into ells (betulini aid derivatives/antiviral drug/envelope/synytlum formation/vfrus-el fusion) JEAN-FRAN(OS MAYAUX*t, ANNE BOUSSEAU*, RUD PAUWELSt, THERRY HUET*, YVETTE H9NN*, NORBERT DEREU*, MCHEL EVERS*, FRANCOSE SOLER*,fCHRSTtLE POUJADE*, ERK DE CLERCQ, AND JEAN-BERNARD LE PECQ* *Rh6ne Poulen Rorer S.A., Centre de Reherhe de Vitry-Alfortville, nstitute for Medial Researh, Katholieke Universiteit Leuven, Minderbroedersstraat 1, B-3 Leuven, Belgium Communiated by Jean-Marie Lehn, January 3, 1994 (reeived for review July 3, 1993) 13 Quai Jules Guesde, B.P. 14, 9443 Vitry Sur Seine Cedex, Frane; and *Rega ABSTRACT A series of triterpene ompounds harateried by a stringent struture-ativity relationship were identified as potent and seletive inhibitors of human immunodefiieny virus type 1 (HV-1) repliation. Currently studied betulini derivatives have 5% inhibitory onentrations (Css) agaehv-1 strain /LA in the 1 nm range in several ellular infetion assays but are inative against HV-2. These ompounds did not signifiantly inhibit the in vitro ativities of several purified HV-l enymes. Rather, they ap ed to blok virus infetion at a postbinding, envelope-dependent step involved in the fusion of the virus to the ell membrane. A survey of the agents that have been desribed to have ativity against human immunodefiieny virus (HV) reveals that only a limited number of the potential viral targets have been takled, the most prominent being reverse transriptase (RT) and protease (1-4). n partiular, the designing and sreening of agents that inhibit virus entry into ells have met with limited suess. Despite high initial hopes, several andidate antagonists based on soluble CD4 have failed either in vitro or in vivo (5, 6). On the other hand, polyanioni ompounds that interfere with virus binding or penetration, in partiular sulfated polymers, are likely to be ineffetive beause their speifiity and bioavailability are poor (7). Here we report on a lass of hemisyntheti ompounds derived from a natural triterpene whih is targeted at HV-1 entry into ells. MATERALS AND METHODS Cell Lines and Virus. Cell lines C8166 (ADP13), U-937 (ADP12), and CEM-4 (ADP6) were obtained from the Medial Researh Counil ADS Direted Programme Reagent Projet, National nstitute for Biologial Standards and Control, Hertfordshire, U.K. CEM4 is a sublone enrihed in CD4 antigen derived from the CEM T-lymphoblastoid tumor ell line. The H9 ell line (HTB176) was obtained from the Amerian Type Culture Colletion. The origins of the virus strains were as follows: LA, EL, and 1LOD were from L. Montagnier (nstitut Pasteur, Paris); NDK (8); MN was from the Medial Researh Counil ADS Reagent Projet; B and RF were from R. C. Gallo (National nstitutes of Health); AP595 and 275 M were isolated from European patients. HV-1 (LA) bathes used for sreening were obtained from filtered (.45 urm) supernatants of CEM lone 11 ells (Pasteur-Mdrieux Sdrums et Vains, Marnes-la- The publiation osts of this artile were defrayed in part by page harge payment. This artile must therefore be hereby marked "advertisement" in aordane with 18 U.S.C solely to indiate this fat. Coquette, Frane). Titers of these preparations were about 14 CCD5 (5%o ell ulture infetive doses)/ml. Cellular Assays for HV nhibition. CEM ells were usually grown at 37C (5% C2) in RPM 164 medium supplemented with 1%o heat-inativated fetal bovine serum, peniillin (1 units/ml), streptomyin (1 rig/ml), and Polybrene (Sigma, 2 pyg/ml). n the routine CEM test, 25-pl samples of eah ompound dilution were distributed in tripliate in 96-well tissue ulture miroplates. Cells (125 p4; 5 x 14 per ml) were then added and suspensions were inubated for 1 hr at 37TC. Cells were infeted with 1 P of virus suspension (1-2 CCD5o) and ultured for 5 days. Cell viability was assessed by the spetrophotometri 3-(4,5-dimethylthiaol-2-yl)-2,5- diphenyltetraolium-based assay (9). Mok-infeted ultures were arried out in parallel to determine the degree of ytotoxiity of the ompounds. p24 ore antigen in ulture supernatants was determined by ELSA (NEK6B kit from New England Nulear). RT ativity was measured by a poly(ra) 3H SPA sintillation proximity assay (NK92 from Amersham). The antiviral assay using MT4 ells was as desribed (1). The effet of ompounds on the kinetis of viral prodution in human peripheral blood mononulear ells (PBMCs) was also assayed. PBMCs from seronegative donors were isolated by Fioll/Hypaque (Pharmaia) and stimulated for 3 days with phytohemagglutinin (2.5 pg/ml; Difo). Cells were then washed three times with medium, pelleted, and inubated with 5-1 CCD5 of virus stok per ml. After 1 hr at room temperature, ells were resuspended in RPM 164 medium ontaining 1%6 fetal bovine serum, 1%6 T-ell growth fators (Lymphoult, Biotest Diagnostis, Danville, NJ), and anti-interferon a neutraliing antibody (Bayer, Wuppertal, F.R.G.) at 8 units/ml. Cells were plated at 16 per ml in six-well ulture plates (Costar) in the presene of the ompound to be tested. At 3, 7, 1, and 14 days after infetion, ultures were harvested and viable ells were examined by trypan blue exlusion. Aliquots of supernatants were froen at -7C until tested for p24 antigen, and ells were resuspended at the same density in omplete fresh medium with the same onentration of the tested drug. Determination of Cytoplasmi Proviral DNA. Shortly after infetion, the proviral DNA obtained from a seletive extration was quantified by PCR amplifiation. H9 ells were preinubated in the presene or absene of the drug to be tested for 1 hr, infeted with HV-1 (LA) at 5 CCDso/ml for 1 hr, and grown in ulture medium for another hour. Cells were then washed intensively, and ytoplasmi proviral DNA was extrated by a digitonin/proteinase K/RNase Abbreviations: AZT, 3'-aido-3'-deoxythymidine; HV, human immunodefiieny virus; PBMC, peripheral blood mononulear ell; scd4, soluble CD4; RT, reverse transriptase. tto whom reprint requests should be addressed. 3564
2 Medial Sienes: Mayaux et al. protool (11). A 152-bp fragment of the gag gene of HV-1 and a 237-bp segment of the mitohondrial ytohrome b gene as a ontrol were amplified by PCR. The absene of nulear genomi DNA was heked on a 336-bp fragment of the (3-globin gene. PCR produts were visualied diretly by fluoresene after eletrophoresis in a 3% NuSieve agarose gel (FMC) and by autoradiography after transfer and hybridiation with speifi internal oligonuleotide probes. Amplifiation produts were quantitated with a digital autoradiography detetor (Pakard), and the perentage of proviral DNA was estimated by taking the ratio of HV-1 gag produt to ytohrome b produt and omparing it with that obtained from untreated ontrol ells. 3'-Aido-3'-deoxythymidine (AZT) was used as a referene ompound. Assays of Viral Enymes. n the exogenous RT assay (12), the reation mixture (5 tl) ontained 5 mm Tris-HCl (ph 8.4), 1 mm MgCl2, 1 mm KCl, 2.2 mm dithiothreitol, 2.5,uM dgtp, and.5% (wt/vol) Triton X-1. The template poly(c) or poly(dc) and the primer (dg)12_18 (Pharmaia) were used at onentrations of 4 and 6 pg/ml, respetively. Reombinant HV-1 RT was used at 1 nm. HV-1 integrase assays were arried out essentially as desribed (13). n brief, reation mixtures ontaining 2 mm Hepes (ph 7.), 1 mm MnCl2, 5 mm NaCl, 1% (vol/vol) glyerol, 1 mm dithiothreitol, bovine serum albumin at.1 mg/mi,.5 pmol of 32P-labeled HV-1 U5-end oligonuleotide substrate, and 5 pmol of purified reombinant HV-1 integrase (14) were inubated at 3 C for 1 hr. Autointegration produts were visualied and quantified by autoradiography after eletrophoresis in a 2%o polyarylamide DNA-sequening gel. For another protool, 15 ng of plasmid DNA (3 kb) was inluded in the reation mixture as a heterologous integration target: in this ase, a 1.2% agarose gel was used (15). The assay for HV-1 protease inhibition was as desribed (16). Time-of-Addition Experiment. Delineation of the drugsensitive phase was determined with MT-4 ells infeted at a high multipliity of infetion, >1, with HV-1 strain B. Compounds were added, at a onentration 5-fold to 1- fold higher than their C5 value in the standard MT-4/3-(4,5- dimethylthiaol-2-yl)-2,5-diphenyltetraolium assay, to parallel ultures (37 C) in mirotiter plates at the indiated time after the addition of virus to the ells. After the last addition, all ells were washed to remove unbound virus, resuspended in the same onentration of ompound, and further inubated for 24 hr. HV-1 p24 ore protein was then quantitated by a sandwih ELSA (DuPont). Virus Binding and Synytium Formation. The interation between reombinant soluble CD4 (scd4) (a gift from D. Klatmann, H6pital de la Pitid, Paris) and HV-1 envelope glyoprotein gp12 (Repligen) was analyed with either a CD4-gpl2O ELSA kit (DuPont) or the reently developed Pro. Natl. Aad. Si. USA 91 (1994) 3565 biosensor tehnology (BAore, Pharmaia) (17). The binding of HV-1 virion partiles to CD4+ ells (CEM) was evaluated by flow ytometry (18) on an ATC 3 fluoresene-ativated ell sorter (ODAM, Wissembourg, Frane) with anti-gp12 (NEA 931, DuPont) or anti-cd4 (OKT4, Ortho Diagnostis) monolonal antibodies. The binding of these mouse monolonal antibodies was revealed with a fluoresein-onjugated goat anti-mouse gg antibody (mmunoteh, Luminy, Frane). n these experiments, aurintriarboxyli aid or scd4 was used as referene ompound and AZT as a negative ontrol. The inhibition of synytium formation was quantified by using a HeLa CD4+ LTR (long terminal repeat)-laz indiator ell line, alled P4. The ytoplasm of these ells turns blue upon treatment after infetion by ell-free virus or after fusion with ells expressing HV-1 Env and Tat proteins (19, 2). n brief, indiator ells (14 per well) were inubated for 24 hr in a mirotiter plate, and pretreated for 1 hr at the desired onentration of ompound. H9/B hronially infeted ells or HL2/3 ells, harboring a defetive provirus but expressing high levels of HV-1 proteins (21), were then added (5 x 13 per well) in the presene ofthe drug. After 24 hr at 37 C, ells were washed, fixed in 1% formaldehyde/.2% glutaraldehyde for 5 min, washed again, and inubated in with 5-bromo-4-hloro- 3-indolyl (-D-galatopyranoside as desribed (2). Blue giant ells were ounted by mirosopi examination at x4 magnifiation. n other experiments, CEM ells (16 per ml) were infeted with reombinant vainia virus expressing either the wild-type HV-1 LA envelope (VV.TG.9-1/gpl2O-41) or an envelope mutated in the leavage site (W.TG.1139/gpl6), at a multipliity of infetion of 2-3 for 1 hr at room temperature (23). Vainia-infeted ells were then grown for 2-24 hr at 37 C in the presene or absene of the tested drug. Observations by light interferene ontrast mirosopy indiated that VV.TG.9-1 effiiently indued the formation of synytia, whereas VV.TG.1139 produed only rosettes harateristi of ellular aggregation mediated by CD4-gpl6O binding. OKT4a monolonal antibody, whih effiiently bloks both events, was used as a referene ompound. RESULTS AND DSCUSSON Certain amide derivatives of betulini aid, a triterpene extrated from plane tree bark (Fig. 1), were initially found to be modest inhibitors of both HV-1 protease in vitro and HV-1 infetion in ellular assays. However, in the ourse of examining ompounds having subsequent hemial modifiations, we unexpetedly deteted a derivative bearing an 11-aminoundeanoi lateral hain (RP734; Fig. 1), whih had lost all measurable antiprotease ativity but was at least 1-fold more potent against HV-1 (LA) in ellular infetion R betulini aid H RP 734 RP 7246 RPR H HN, HN, H 1 HH HN O Strutures of betulini aid derivatives. Compound RPR 13611, N'-{N-[3b-hydroxyl-2(29)-ene-28-oyl]-8-aminootanoyl-L-statine FG. 1. (moleular weight, ; melting point, 158 C) was synthesied by a five-step proedure starting from betulini aid, with an overall yield of 31% (22). HO
3 3566 Medial Sienes: Mayaux et al. 1 8 le O 8-8 E C RPR (M) Betulini derivatives (jig/ml) days FG. 2. Anti-HV-1 ativity of betulini aid derivatives in ellular assays. (A) Ativity against the LA strain of HV-1 grown in CEM-4 ells. The index of protetion from HV-1 ytopathi effet (o) is shown together with the inhibition of viral prodution in the supernatant as estimated from both p24 (o) and RT ativity (n) measurements. The effet of the produt on ell viability is indiated (A). (B) Comparative ativities in the MT-4 antiviral assay as estimated from the protetion index against HV-1 (HB) ytopathi effet for RP 734 (A), RP 7246 (A), and RPR (o). The ativity of RPR against HV2 (ROD) in the same assay (v) is shown for omparison. As in A, the 1%/6 protetion level orresponds to the value observed without any ompound or virus added to the ulture. (C) Ativities of betulini derivatives against aute HV-1 (LA) infetion in PBMCs. The kinetis of viral expression measured by the prodution of p24 antigen in the supernatant are indiated in the absene (o) or presene of 1 pm RP 7246 (o), RPR (o), or AZT (A). assays (Cso Pro. NatL Aad Si. USA 91 (1994).3,uM) than the original ompounds. Struture-ativity relationships for this series of derivatives suggested a rather stringent speifiity. n partiular, analogous derivatives of other tested natural triterpenes were inative, an optimal length of the lateral hain was needed, and several positions on the moleule ould not be modified, even slightly, without signifiant loss of ativity (unpublished work). Chemial optimiation of the lateral hain resulted in more potent ompounds, represented by RPR (Figs. 1 and 2B), the mehanism of whih was further studied. The effet of betulini derivatives in ellular infetion assays is shown in Fig. 2. Effiient protetion from the virus-indued ytopathi effet was observed in various ell lines. Similar effiienies were observed with CEM ells, for whih an important single-ell killing omponent is usually observed (9, 24), and with MT-4 ells transfeted with 1 proviral DNA of human T-lymphoyti virus type, where the formation of synytia ontributes to the development of the ytopathi effet (1). ndeed, this effet is aompanied by a suppression of virus prodution, measured either as RT ativity or as the onentration of p24 antigen in the ulture supernatant (Fig. 2A). We also heked the ativity of the ompounds in several other ell lines, inluding the monoyti ell line U-937, and in peripheral blood lymphoytes (Table 1 and Fig. 2C). C5 values for RPR varied between 4 and 1 nm in most ell systems, with seletively indexes in exess of 1. [The preise assessment of ytotoxi onentrations (CC5o) for some betulini derivatives an be hampered by the limited solubility of these ompounds above 1 pm (formation of gels), depending on experimental onditions.] n addition to HV-1 strain B, betulini de- A rivatives were also found to be ative against laboratory ) strains MN and RF, as well as against several HV-1 linial isolates. However, no signifiant ativity ould be found against HV-2 (ROD and EHO isolates) when RPR was tested under the same onditions as those used for HV-1 strain UB/LA, showing that the ativity of the betulini derivatives tested is restrited to HV-1 (Fig. 2B). Evidene that the speifiity for these ompounds ould be restrited even within the HV-1 family was supplied by the observation that most ompounds ative against UB/LA were not ative, or muh less ative, against two isolates of Zairian origin, NDK and EL (Table 1). Thus, betulini derivatives apparently interfere with a very speifi moleular event of the repliation yle. Table 1. Anti-HV ativity of RPR in various ell ultures Virus Strain Cell C5, PM S HV-1 LA or TB CEM-4.58 >2 MT-4.45 >2 H9.3 >9 C >1 U >125 PBMCs <.1 >3 MN MT-4.4 >2 RF MT-4.75 >15 NDK CEM-4, MT-4 >5 <1 EL CEM-4 >5 <1 APO 595 PBMC.2 >5 275 M MT-4.14 >7 HV-2 ROD MT-4 >1 <1 EHO MT-4 >1 <1 Data represent mean values for two to nine experiments. Cso represents the 5%1o inhibitory onentration for the ytopathogeniity ofhv (CEM-4, MT-4, C8166) or for the prodution ofrt ativity or p24 ore antigen (H9, U-937, PBMCs). The seletivity index (S) orresponds to the ratio CCso/Cso, where CC5o is the 5%6 ytotoxi onentration for mok-infeted ells. n the ase of LA in PBMCs, the lowest tested onentration was.1 pm and gave >5% inhibition.
4 Ative derivatives were also examined for a possible inhibition of the in vitro ativity of several purified HV-1 enymes. No inhibition of RT, integrase, or protease was deteted at onentrations of the derivatives ompatible with ellular ativity (data not shown), suggesting that the orresponding steps were not involved in the inhibitory mehanism of these ompounds. n fat, evidene was obtained from two different experiments that betulini derivatives at at an early stage in the infetious yle. First, we observed a lear dose-dependent inhibitory effet of ompounds at miromolar onentrations on the synthesis of proviral ytoplasmi DNA, as measured by PCR only 2 hr after the onset of infetion (data not shown). Seond, we studied the influene of delaying the addition of ompounds at various times soon after the exposure of MT-4 ells to HV-1. Suh an experiment showed (Fig. 3A) that postponing the addition of RPR for 1 hr was enough to anel the inhibitory poteny of this ompound on the subsequent prodution of viral antigens. Betulini derivatives behaved in this partiular experiment very similarly to agents that interfere with the binding of virus to ells, suh as sulfated polysaharides, or to ompounds proposed to interat with a viral unoating i 1 Medial Sienes: Mayaux et al. Pro. Natl. Aad. Si. USA 91 (1994) 3567 event, suh as biylams (25). n fat, that the betulini derivatives affet virus binding was ruled out by several experiments showing that betulini derivatives did not signifiantly inhibit either the binding of the virus to CD4 ells (Fig. 4A) or the binding of scd4 to gpl2 (Fig. 4B). Proof for the mehanism of ation ame from assays designed to monitor synytium formation between uninfeted CD4 ells and hronially HV-1-infeted ells or ells expressing the HV-1 envelope. Betulini derivatives effiiently bloked the formation of synytia indued by HV-1 strain B (Fig. 3B) but not the formation of giant ells indued by the NDK strain (R.P., unpublished data; the lak of ativity in HV-1 strain NDK-dependent synytia assays orrelates well with the ineffiay of this ompound against the NDK isolate in A (n Li- w a C b d. C m._._ m C.._= Time of addition of ompound (min) FG. 3. Betulini aid derivatives at at an early step of the virus presene of the speifi anti-gpl2 antibody. (a) Control without infetion :yle. (A) Variation ofp24 antigen prodution with the time ompound. (b) nhibition of gpl2 binding by aurintriarboxyli aid of additia)n of the inhibitory ompound. Control infetion was (1 ug/ml). ( and d) Lak of inhibition of gpl2 binding by betulini provided by the addition of ompound-free medium (n). During the aid derivatives (1,M) RP 7246 and RPR 13611, respetively. n studied titme frame, AZT (.5 ug/ml; o) was always protetive. n the same onditions, scd4 was ative, whereas AZT had no effet these oknlitions, RPR (1 pg/ml; o) ould not be distinguished (data not shown). (B) Quantifiation of binding of the human serum from dextiran sulfate (5 pg/ml; *) or from the biylam ompound albumin (HSA)-CD4 fusion protein (26) to gpl2 using biosensor JM2763 (: 2 pg/ml; A): all three ompounds lost their protetive tehnology. Briefly, HSA-CD4 binds to immobilied gpl2 on the apaity. after about 1 hr. (B) nhibition of synytium formation sensor hip and the signal an be further amplified by anti-hsa mediated by either H9/B (open symbols) or HL2/3 (filled sym- polylonal antibody. The ontrol (without ompound) defines 1% bols) withi the P4 indiator ell line. The effet of RPR binding. Soluble CD4 (2.2,uM) and aurintriarboxyli aid (ATA, 5 (squares) is shown in omparison with that of dextran sulfate,um) inhibit the gpl2o-cd4 interation whereas betulini aid del. n these onditions, AZT was ompletely inative (ir- rivatives RP 734, RP 7246, and RPR at 1,uM had no (triangles) les), evein with the hronially infeted ells. effet. B L RELATVE FLUORESCENCE UNTS Control scd4 ATA COMPOUNDS off 'W..m *W...mj..s. FG. 4. Betulini aid derivatives do not blok virus binding. (A) 1 O.2 1 O Flow ytofluorimetri analysis of the binding of HV-1 LA virions to CD4+ CEM ells. Open profile, fluoresene intensity of the nhibitor (pg/rml) negative ontrol orresponding to CEM ells inubated with fluoresein-onjugated antibody only; filled profile, fluoresene in the.o
5 3568 Medial Sienes: Mayaux et al. ellular infetion assays). More speifi synytium assays were arried out by using reombinant vainia viruses expressing either the normal envelope from strain HV-1 LA or an unleavable mutant gpl6 protein (23). Ative betulini derivatives at submiromolar onentrations inhibited the envelope-dependent synytium formation but did not blok the formation of aggregates observed when the envelope variant was used (data not shown). Finally, the ompounds at ative onentrations did not exert a diret viriidal effet, sine preinubation of the virus with the ompounds did not modify its subsequent infetive apaity. Together, these results provide evidene that the betulini derivatives studied blok virus infetion at a postbinding step neessary for virus-membrane fusion and that the target of these ompounds is ontained within, or interats with, the HV-1 envelope gpl2/gp4l. This is, to our knowledge, the first desription of a nonpeptidi ompound having this potential, sine, until now, only monolonal antibodies or peptides have been shown to seletively affet the HV-1 membrane fusion step (27, 28). However, drugs that blok fusion events indued by ertain myxoviruses have been desribed-for example, amantadine in the ase of influena A (reviewed in ref. 29). Unlike the relatively well-known gp12o-cd4 binding, the postbinding moleular events leading to HV-1 envelopemediated membrane fusion are muh less well understood but are likely to be harateried by major onformational hanges of the whole gpl2/gp4l omplex, ultimately resulting in the produtive exposure of the gp4l N-terminal fusogeni domain. This mehanism is important not only for the penetration of free virus into ells but also for ell fusion proesses that an lead to synytium formation, an important determinant of in vitro ytopathogeniity, as well as ell-toell viral dissemination (3, 31). Studies have mapped elements of the gpl2 and gp4l glyoproteins essential for effiient membrane fusion (32); it will be important to determine whih of these peptides is affeted by the inhibitory mehanism of betulini aid derivatives. Beause of their mode of ation, the potential linial usefulness of these agents in treating HV-1 disease deserves further investigation. We thank M. P. Kieny and M. Mehtali (Transgene, Strasbourg) for their most effiient help with the reombinant vainia viruses, P. Charneau (nstitut Pasteur) for his gift of the P4 laz indiator ell line, and M. Lemaltre (Eurogente, Liege, Belgium) for his partiipation in the initial phase of this study. The tehnial assistane of F. Destouesse, F. Begassat, C. Chong, L. Luarain, and N. Meritet is gratefully aknowledged. We thank S. Reboul and A. Mury-Brelier for help with the scd4-gpl2o binding assays, M. Maratrat for the flow ytometry experiments, and K. Pepper for ritial reading ofthe manusript. 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