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Lindsay Lundberg, Chelsea Pinkham, Cynthia de la Fuente, Ashwini Brahms, Nazly Shafagati, Kylie M. Wagstaff, David A. Jans, Sharon Tamir, Kylene Kehn-Hall
Selective Inhibitor of Nuclear Export (SINE) Compounds Alter New World Alphavirus Capsid Localization and Reduce Viral Replication in Mammalian Cells
www.plosntds.org
www.plosntds.org
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(the)Tj
1.4683 0 Td
(aim)Tj
1.7405 0 Td
(of)Tj
1.0148 0 Td
(inhibiting)Tj
4.1839 0 Td
(viral)Tj
1.9956 0 Td
(replication)Tj
4.524 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1203 0 Td
(proposed)Tj
3.9514 0 Td
(by)Tj
1.1849 0 Td
(others)Tj
2.7099 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(23)Tj
0 g
(].)Tj
-33.7887 -1.2983 Td
(Inhibitors)Tj
4.2122 0 Td
(previously)Tj
4.354 0 Td
(demonstrated)Tj
5.76 0 Td
(to)Tj
1.0261 0 Td
(modulate)Tj
4.0025 0 Td
(viral)Tj
1.9956 0 Td
(protein)Tj
3.1521 0 Td
(binding)Tj
3.3505 0 Td
(to)Tj
1.0261 0 Td
(importin)Tj
/F11 1 Tf
3.8154 0 Td
()Tj
/F6 1 Tf
0.7881 0 Td
(and)Tj
/F11 1 Tf
1.7291 0 Td
()Tj
/F6 1 Tf
(1,)Tj
-35.2117 -1.3039 Td
(mifepristone)Tj
5.312 0 Td
([)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(])Tj
1.8482 0 Td
(and)Tj
1.7348 0 Td
(ivermectin)Tj
4.5127 0 Td
([)Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
(],)Tj
2.0807 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4683 0 Td
(well-documented)Tj
7.2 0 Td
(CRM1)Tj
2.8743 0 Td
(inhibitor,)Tj
4.0025 0 Td
(Leptomycin)Tj
-32.7626 -1.2983 Td
(B)Tj
0.7993 0 Td
([)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(28)Tj
0 g
(],)Tj
3.5433 0 Td
(altered)Tj
2.948 0 Td
(the)Tj
1.4683 0 Td
(cellular)Tj
3.1408 0 Td
(distribution)Tj
4.9663 0 Td
(of)Tj
1.0148 0 Td
(VEEV)Tj
2.7496 0 Td
(capsid,)Tj
2.9707 0 Td
(reduced)Tj
3.4469 0 Td
(viral)Tj
1.9955 0 Td
(replication,)Tj
4.7452 0 Td
(and)Tj
-33.7887 -1.2983 Td
(increased)Tj
3.9968 0 Td
(cell)Tj
1.559 0 Td
(survival.)Tj
3.566 0 Td
(As)Tj
1.2642 0 Td
(expected,)Tj
3.9458 0 Td
(mifepristone)Tj
5.3121 0 Td
(and)Tj
1.7348 0 Td
(ivermectin)Tj
4.5127 0 Td
(kept)Tj
1.9559 0 Td
(capsid)Tj
2.7496 0 Td
(primarily)Tj
3.9742 0 Td
(cyto-)Tj
-34.5711 -1.3039 Td
(plasmic,)Tj
3.5149 0 Td
(while)Tj
2.3641 0 Td
(Leptomycin)Tj
5.0229 0 Td
(B)Tj
0.7994 0 Td
(trapped)Tj
3.3052 0 Td
(capsid)Tj
2.7552 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4684 0 Td
(nucleus.)Tj
3.5036 0 Td
(Altering)Tj
3.5262 0 Td
(capsid)Tj
2.7496 0 Td
(localization)Tj
-30.0413 -1.2982 Td
(reduced)Tj
3.4412 0 Td
(viral)Tj
1.9956 0 Td
(titers)Tj
2.2393 0 Td
(of)Tj
1.0148 0 Td
(both)Tj
2.058 0 Td
(the)Tj
1.474 0 Td
(VEEV)Tj
2.7439 0 Td
(vaccine)Tj
3.1974 0 Td
(strain,)Tj
2.727 0 Td
(VEEV-TC83,)Tj
5.5502 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4683 0 Td
(wild-type)Tj
3.9912 0 Td
(strain,)Tj
-33.63 -1.2983 Td
(Trinidad)Tj
3.7757 0 Td
(Donkey)Tj
3.3845 0 Td
(\(VEEV-TrD\).)Tj
5.7203 0 Td
(Interestingly,)Tj
5.4935 0 Td
(inhibitor)Tj
3.7814 0 Td
(treatment)Tj
4.1386 0 Td
(also)Tj
1.7631 0 Td
(increased)Tj
4.0025 0 Td
(cellular)Tj
3.1408 0 Td
(via-)Tj
-35.2004 -1.3039 Td
(bility)Tj
2.2563 0 Td
(in)Tj
1.0375 0 Td
(infected)Tj
3.4185 0 Td
(cells)Tj
1.9219 0 Td
(compared)Tj
4.2463 0 Td
(to)Tj
1.0261 0 Td
(infected)Tj
3.4186 0 Td
(cells)Tj
1.9219 0 Td
(treated)Tj
2.9933 0 Td
(with)Tj
2.0013 0 Td
(the)Tj
1.4683 0 Td
(vehicle)Tj
2.9877 0 Td
(only)Tj
1.9729 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(].)Tj
2.0806 0 Td
(However,)Tj
-32.7512 -1.2983 Td
(the)Tj
1.4683 0 Td
(traditional)Tj
4.422 0 Td
(CRM1)Tj
2.8686 0 Td
(inhibitor,)Tj
4.0082 0 Td
(Leptomycin)Tj
5.0173 0 Td
(B,)Tj
1.0261 0 Td
(is)Tj
0.8504 0 Td
(cytotoxic,)Tj
4.0876 0 Td
(creating)Tj
3.4525 0 Td
(the)Tj
1.4684 0 Td
(need)Tj
2.143 0 Td
(for)Tj
1.3889 0 Td
(a)Tj
0.652 0 Td
(new)Tj
1.8765 0 Td
(gener-)Tj
-34.7298 -1.2982 Td
(ation)Tj
2.2733 0 Td
(of)Tj
1.0148 0 Td
(CRM1)Tj
2.8743 0 Td
(inhibitors.)Tj
-4.9662 -1.2983 Td
(Karyopharm)Tj
5.3347 0 Td
(Therapeutics)Tj
5.4028 0 Td
(has)Tj
1.5421 0 Td
(discovered)Tj
4.507 0 Td
(potent,)Tj
3.0387 0 Td
(small)Tj
2.3301 0 Td
(molecule,)Tj
4.0592 0 Td
(orally)Tj
2.4831 0 Td
(available,)Tj
3.8891 0 Td
(slowly)Tj
-33.783 -1.3039 Td
(reversible)Tj
4.0705 0 Td
(inhibitors)Tj
4.1385 0 Td
(of)Tj
1.0148 0 Td
(CRM1,)Tj
3.1011 0 Td
(termed)Tj
3.0841 0 Td
(selective)Tj
3.5376 0 Td
(inhibitor)Tj
3.7814 0 Td
(of)Tj
1.0148 0 Td
(nuclear)Tj
3.1975 0 Td
(export)Tj
2.8006 0 Td
(\(SINE\))Tj
3.0217 0 Td
(com-)Tj
-32.7626 -1.2983 Td
(pounds.)Tj
3.4355 0 Td
(The)Tj
1.7802 0 Td
(most)Tj
2.2053 0 Td
(advanced)Tj
3.9968 0 Td
(drug)Tj
2.109 0 Td
(in)Tj
1.0375 0 Td
(this)Tj
1.6724 0 Td
(class)Tj
2.0466 0 Td
(is)Tj
0.8447 0 Td
(selinexor,)Tj
4.0592 0 Td
(which)Tj
2.6532 0 Td
(is)Tj
0.8447 0 Td
(currently)Tj
3.8891 0 Td
(under)Tj
2.6192 0 Td
(clinical)Tj
-33.1934 -1.2983 Td
(investigation)Tj
5.3574 0 Td
(for)Tj
1.389 0 Td
(the)Tj
1.4683 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
1.0148 0 Td
(patients)Tj
3.3675 0 Td
(with)Tj
1.9956 0 Td
(advanced)Tj
3.9911 0 Td
(hematologic)Tj
5.142 0 Td
(and)Tj
1.7292 0 Td
(solid)Tj
2.1316 0 Td
(malignancies)Tj
-31.7251 -1.3039 Td
(\(ClinicalTrials.gov)Tj
7.5968 0 Td
(identifier:)Tj
4.1272 0 Td
(NCT01986348\).)Tj
6.6047 0 Td
(After)Tj
2.2847 0 Td
(administration)Tj
6.1681 0 Td
(to)Tj
1.0261 0 Td
(over)Tj
1.9729 0 Td
(1400)Tj
2.126 0 Td
(patients)Tj
3.3676 0 Td
(as)Tj
1.0148 0 Td
(of)Tj
-36.2889 -1.2982 Td
(February)Tj
3.838 0 Td
(2016,)Tj
2.3471 0 Td
(selinexor)Tj
3.8324 0 Td
(\(KPT-330\))Tj
4.5184 0 Td
(is)Tj
0.8504 0 Td
(showing)Tj
3.583 0 Td
(preliminary)Tj
4.9379 0 Td
(evidence)Tj
3.7134 0 Td
(of)Tj
1.0148 0 Td
(durable)Tj
3.2598 0 Td
(anti-tumor)Tj
-31.8952 -1.2983 Td
(activity)Tj
3.118 0 Td
(in)Tj
1.0318 0 Td
(multiple)Tj
3.566 0 Td
(cancer)Tj
2.846 0 Td
(types.)Tj
2.5001 0 Td
(SINE)Tj
2.3414 0 Td
(compounds)Tj
4.9606 0 Td
(are)Tj
1.4513 0 Td
(well)Tj
1.8199 0 Td
(tolerated)Tj
/F10 1 Tf
3.7474 0 Td
[()12(\n)]TJ
1.0148 0 Td
[()-13()14()7()20()]TJ
/F6 1 Tf
2.0466 0 Td
(and)Tj
/F10 1 Tf
1.7291 0 Td
[()12(\n)]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8198 0 Td
([)Tj
0.83 0.64 0.02 0 k
(29)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
-35.0076 -1.3039 Td
(30)Tj
0 g
(],)Tj
1.7347 0 Td
(and)Tj
1.7292 0 Td
(some)Tj
2.33 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(compounds)Tj
4.955 0 Td
(can)Tj
1.627 0 Td
(cross)Tj
2.2451 0 Td
(the)Tj
1.4683 0 Td
(blood-brain)Tj
4.9946 0 Td
(barrier)Tj
2.965 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(].)Tj
2.075 0 Td
(Due)Tj
1.9105 0 Td
(to)Tj
1.0262 0 Td
(previous)Tj
3.6453 0 Td
(suc-)Tj
-35.1947 -1.2983 Td
(cesses)Tj
2.5738 0 Td
(in)Tj
1.0318 0 Td
(several)Tj
2.9367 0 Td
(viral)Tj
1.9955 0 Td
(models)Tj
3.1011 0 Td
(and)Tj
1.7292 0 Td
(their)Tj
2.1089 0 Td
(tolerability)Tj
4.5411 0 Td
(in)Tj
1.0375 0 Td
(human)Tj
3.0784 0 Td
(cancer)Tj
2.8403 0 Td
(clinical)Tj
3.0784 0 Td
(trials)Tj
2.1996 0 Td
([)Tj
0.83 0.64 0.02 0 k
(31)Tj
0 g
(],)Tj
2.075 0 Td
(three)Tj
-34.3273 -1.2983 Td
(active)Tj
2.5171 0 Td
(compounds,)Tj
5.1874 0 Td
(referred)Tj
3.4185 0 Td
(to)Tj
1.0262 0 Td
(henceforth)Tj
4.558 0 Td
(as)Tj
1.0148 0 Td
(KPT-185,)Tj
4.0706 0 Td
(KPT-335,)Tj
4.0648 0 Td
(and)Tj
1.7291 0 Td
(KPT-350,)Tj
4.0706 0 Td
(which)Tj
2.6475 0 Td
(are)Tj
1.4513 0 Td
(ana-)Tj
-35.7559 -1.2982 Td
(logs)Tj
1.7971 0 Td
(of)Tj
1.0148 0 Td
(selinexor,)Tj
4.0592 0 Td
(and)Tj
1.7291 0 Td
(one)Tj
1.7008 0 Td
(inactive)Tj
3.3392 0 Td
(control)Tj
3.1181 0 Td
(compound,)Tj
4.8245 0 Td
(KPT-301,)Tj
4.0649 0 Td
(were)Tj
2.1259 0 Td
(tested)Tj
2.5512 0 Td
(for)Tj
1.3833 0 Td
(antiviral)Tj
3.5433 0 Td
(activ-)Tj
-35.2514 -1.3039 Td
(ity)Tj
1.2415 0 Td
(against)Tj
3.0274 0 Td
(three)Tj
2.262 0 Td
(New)Tj
2.0636 0 Td
(World)Tj
2.8403 0 Td
(alphaviruses.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 304.2141 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Methods)Tj
/F0 1 Tf
0 -1.5023 Td
(CRM1)Tj
3.0283 0 Td
(inhibitors)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 269.1779 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(The)Tj
1.7801 0 Td
(selective)Tj
3.5433 0 Td
(CRM1)Tj
2.8743 0 Td
(inhibitors)Tj
4.1386 0 Td
(KPT-335,)Tj
4.0705 0 Td
(KPT-350,)Tj
4.0648 0 Td
(KPT-185,)Tj
4.0649 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.474 0 Td
(inactive)Tj
3.3335 0 Td
(trans-enantio-)Tj
-31.0731 -1.2982 Td
(mer)Tj
1.8311 0 Td
(KPT-301)Tj
3.8438 0 Td
(were)Tj
2.1203 0 Td
(provided)Tj
3.8154 0 Td
(by)Tj
1.1849 0 Td
(Karyopharm)Tj
5.3291 0 Td
(Therapeutics)Tj
5.4084 0 Td
(\(Newton,)Tj
3.9798 0 Td
(MA\).)Tj
2.3641 0 Td
(KPT-185)Tj
3.8438 0 Td
(was)Tj
1.6951 0 Td
(char-)Tj
-35.4158 -1.2983 Td
(acterized)Tj
3.7984 0 Td
(most)Tj
2.211 0 Td
(extensively)Tj
4.5864 0 Td
(in)Tj
/F10 1 Tf
1.0318 0 Td
[()12(\n)]TJ
1.0148 0 Td
[()-13()14()7()20()]TJ
/F6 1 Tf
2.0466 0 Td
(assays,)Tj
2.8516 0 Td
(but)Tj
1.5534 0 Td
(has)Tj
1.542 0 Td
(poor)Tj
2.1203 0 Td
(PK)Tj
1.457 0 Td
(properties)Tj
4.2747 0 Td
(unsuitable)Tj
4.3596 0 Td
(for)Tj
1.389 0 Td
(use)Tj
/F10 1 Tf
1.5307 0 Td
[()12(\n)]TJ
-35.7673 -1.3039 Td
[()-13()15()3()]TJ
/F6 1 Tf
(.)Tj
2.0466 0 Td
(KPT-335)Tj
3.838 0 Td
(\(verdinexor\))Tj
5.2611 0 Td
(and)Tj
1.7291 0 Td
(-350)Tj
1.9956 0 Td
(are)Tj
1.4513 0 Td
(less)Tj
1.6101 0 Td
(potent)Tj
2.8176 0 Td
(against)Tj
3.0274 0 Td
(CRM1)Tj
2.8687 0 Td
(than)Tj
2.0295 0 Td
(KPT-185,)Tj
4.0706 0 Td
(but)Tj
1.5533 0 Td
(have)Tj
-34.2989 -1.2983 Td
(similar)Tj
2.9876 0 Td
(specificity,)Tj
4.4334 0 Td
(good)Tj
2.228 0 Td
(oral)Tj
1.7802 0 Td
(bioavailability)Tj
5.811 0 Td
(and)Tj
1.7291 0 Td
(good)Tj
2.228 0 Td
(tolerability,)Tj
4.7622 0 Td
(thereby)Tj
3.2258 0 Td
(are)Tj
1.4513 0 Td
(suitable)Tj
3.2825 0 Td
(for)Tj
-33.9191 -1.2982 Td
(future)Tj
/F10 1 Tf
2.6532 0 Td
[()12(\n)]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8198 0 Td
(studies.)Tj
3.2145 0 Td
(KPT-335)Tj
3.8437 0 Td
(\(verdinexor\))Tj
5.2554 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1259 0 Td
(tested)Tj
2.5512 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.6519 0 Td
(Phase)Tj
2.5228 0 Td
(1)Tj
0.6974 0 Td
(healthy)Tj
3.1351 0 Td
(volunteer)Tj
-32.0653 -1.2983 Td
(clinical)Tj
3.0727 0 Td
(trial)Tj
1.8368 0 Td
(and)Tj
1.7348 0 Td
(found)Tj
2.6192 0 Td
(to)Tj
1.0205 0 Td
(be)Tj
1.1508 0 Td
(safe)Tj
1.7292 0 Td
(and)Tj
1.7291 0 Td
(well-tolerated)Tj
5.7033 0 Td
(\(ClinicalTrials.gov)Tj
7.5968 0 Td
(Identifier:)Tj
-28.1932 -1.3039 Td
(NCT02431364\).)Tj
6.599 0 Td
(KPT-350)Tj
3.8437 0 Td
(has)Tj
1.5421 0 Td
(a)Tj
0.6519 0 Td
(higher)Tj
2.8063 0 Td
(brain)Tj
2.3471 0 Td
(penetration)Tj
4.8529 0 Td
(ratio)Tj
2.0976 0 Td
(than)Tj
2.0296 0 Td
(KPT-335)Tj
3.8437 0 Td
(\(verdinexor\).)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 139.011 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Cell)Tj
1.9134 0 Td
(culture)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 122.0031 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Vero)Tj
2.2166 0 Td
(cells)Tj
1.9162 0 Td
(and)Tj
1.7348 0 Td
(mouse)Tj
2.8573 0 Td
(embryonic)Tj
4.5411 0 Td
(fibroblasts)Tj
4.3653 0 Td
(\(MEFs\))Tj
3.2542 0 Td
(were)Tj
2.1203 0 Td
(maintained)Tj
4.7905 0 Td
(as)Tj
1.0148 0 Td
(described)Tj
4.0535 0 Td
(previously)Tj
-32.8646 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(].)Tj
2.0749 0 Td
(BHK-J)Tj
2.9197 0 Td
(cells)Tj
1.9218 0 Td
(were)Tj
2.126 0 Td
(maintained)Tj
4.7849 0 Td
(at)Tj
0.9524 0 Td
(37C,)Tj
2.4548 0 Td
(5%)Tj
1.4513 0 Td
(CO)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 400.9889 107.3196 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 406.7149 109.0204 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(in)Tj
1.0374 0 Td
(Eagle's)Tj
2.931 0 Td
(Minimum)Tj
4.3654 0 Td
(Essential)Tj
3.7303 0 Td
(Medium)Tj
-32.7342 -1.3039 Td
(\(EMEM\))Tj
3.8211 0 Td
(\(ATCC,)Tj
3.4072 0 Td
(Manassas,)Tj
4.2747 0 Td
(VA,)Tj
1.8255 0 Td
(302003\))Tj
3.9288 0 Td
(supplemented)Tj
5.8562 0 Td
(with)Tj
1.9956 0 Td
(7.5%)Tj
2.1543 0 Td
(fetal)Tj
1.9105 0 Td
(bovine)Tj
2.9254 0 Td
(serum)Tj
2.7269 0 Td
(\(FBS\))Tj
-34.8262 -1.2982 Td
(and)Tj
1.7292 0 Td
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