Abstract
In this study, the effects of side-chain configurations of D-Ile residues of a retro–inverso (RI)-type inhibitor on the human T-cell leukemia virus type 1 (HTLV-1) protease containing a hydroxyethylamine dipeptide isostere were clarified. Prior to evaluation using the RI-type inhibitor, the effects of side-chain configurations of Ile residues of the substrate peptide on the HTLV-1 protease were examined to estimate the influence of side-chain configurations on enzyme activity. Based on the estimation of the influence of side-chain configurations on protease affinity, the RI-type inhibitors containing a D-allo-Ile residue in the corresponding substrate sequence, instead of a D-Ile residue, were synthesized via 9-fluorenylmethoxycarbonyl-based solid-phase peptide synthesis. Refolded recombinant HTLV-1 protease (1-116, L40I) was used for the simple and short evaluation of the inhibitory activities of the synthesized RI-type inhibitors. The results clearly indicated that mimicking the whole topology, comprising both the main- and side-chain structures of the parent inhibitor, is effective for the design of potent RI-modified protease inhibitors.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1), the first reported human retrovirus, was isolated from adult patients with T-cell leukemia/lymphoma in 1980 [1]
HTLV-1 protease is a key protease in the replication of the virus; it is similar to the human immunodeficiency virus (HIV)-1 protease in acquired immune deficiency syndrome and is believed to be a suitable target for the development of inhibitors for therapeutic use, a clinically effective inhibitor of HTLV-1 protease has not been developed
We previously reported the synthesis and structure–activity relationships of HTLV-1 protease inhibitors containing a transition state mimic, the hydroxyethylamine dipeptide isostere [4]
Summary
Human T-cell leukemia virus type 1 (HTLV-1), the first reported human retrovirus, was isolated from adult patients with T-cell leukemia/lymphoma in 1980 [1]. Dues at the P3–P1 sites, corresponding to the substrate sequence at the N terminal of the scissile position, form the core sequence for inhibitory activity. Based on these results, we cinortroesdpuocnedinagDt-oamthiensouabcsitdr,atinessteeqaudeonfcethaet pthaereNntteLr-maminianlooafctihde, sincitsositlheispocosirteiosne,qfuoernmcethteo cimorpersoevqeuetnhcee finor vinivhoibisttoarbyilaictytivoitfy.thBeasesudbosntrtahtes-bearseesdultHs,TwLeVi-n1trpodroutceeadsea Din-haimbitnoor aacnidd, idnesmteoadnsotrfattheedp, aforerntthLe-faimrsitntoimacei,dt,hianttothtehirsectorore–isnevqeuresnoc(eRtIo) immopdriofviceatihoeninofvaivnoisnthaibbiiltitoyr ocfonthtaeisnuinbgstraattrea-nbasisteiodnHsTtaLtVe-m1 pimroictecaasne irnehtaiibnitionrhainbidtodreymaoctnisvtirtayte[7d],. Autoproteolysis by the refolded protease yields degraded fragments during the production of HTLV-1 protease by the recombinant procedure using E. coli. A mutation of Leu. precursor protein to produce HTLV-1 protease and several other proteins necessary for the reproduction of viral particles [17]. Autoproteolysis by the refolded protease yields degraded fragments during the production of HTLV-1 proteas3eobf y12 the recombinant procedure using E. coli. Aprlothteoausgeh, wthheicahtaslhyotiwc seftfhicaitetnhceyt(ukrcant/oKvme)r ooffththeererecocommbbininanant tprportoetaesaesewiasslaopwperroxthimanattehlyat8o0f%thoef tshyanttohfetthice pchroetmeaicsael.lyAslythnothuegshiztehde pcraotatelyastiec, ethffiecfioelndceyd(rkeccaot/mKbmin) aonftthperorteecaosme bshinoawnetdprsoutfefiacsienwt apsoatepnpcryoxfoimr uasteliyn8t0h%e soufbtshea-t qoufetnhteecvhaelmuaictiaollnyosfysnytnhtehsiezteicdspurbostteraaste,stahnedfoinldheidbirtoecrsomwbitihnoaunt tphreoteimasee-csohnoswuemdisnugf,fiicnideni-t vpiodtueanlcryeffoorlduisneginprtohceesduubrseerqeuqeunitreedvailnupatrieovnioouf ssyenxtpheertiimc seunbtss.trates and inhibitors without the time-consuming, individual refolding procedure required in previous experiments
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