Table 1.

Status of small molecule drugs developed for filovirus infection.

Targeted step of virus lifecycle	Small Molecule	MOAa	Efficacy in vitro	Efficacy in vivo	Clinical Trialb
RNA synthesis	BCX4430[43]	Inhibition of viral RdRp - chain terminator	IC50 3.4–11.8 μMc,d,e,f IC90 10.3–25.4 μMc,d,e,f	Protection in mice, guinea pigs. NHPs: 15 mg/kg, twice daily via i.m.g confers protection against MARV when administered up to 48hr post-infection.	Phase I (NCT02319772, completed; NCT03800173, recruiting)
	GS-5734[42]	Inhibition of viral RdRp - chain terminator	IC50 0.06–0.14 μMd,h,i IC90 0.18–0.41 μMd,h,i	Confers complete protection in NHPs against EBOV when administered 72hr post-infection at a 10 mg/kg loading dose followed by 3 or 10 mg/kg daily dose i.v.j	Phase II (NCT02818582, recruiting)
	Favipiravir[41,48,49]	Either inhibition of viral RdRp and/or causes lethal mutagenesis	IC50 67 μMd,k IC90 110 μMd,k	Complete protection of IFNAR knockout mice, immunocompetent C57BL/6 mice. NHPs: Three p.o.l dosing regimens (400 mg/kg loading dose at day −3 followed by 200 mg/kg daily, 250 mg/kg loading dose at day 0 followed by 150 mg/kg twice daily, 125 mg/kg loading dose at day 0 followed by 75 mg/kg twice daily) protected 1 of 18 EBOV infected NHPs, despite plasma levels above EC50 values. I.V. dosing of a 250 mg/kg loading dose followed by 150 mg/kg twice daily protected 5 of 6 MARV infected NHPs.	Phase III (influenza, NCT02008344, completed) Phase II (EBOV, NCT02329054, completed; NCT02662855, completed)
	3-deazaneplanocin A[52,53]	Inhibition of SAH hydrolase	IC50 2 μMd,k	Complete protection of BALB/c mice against MA-EBOVaa when treated once with 1 mg/kg up to 48hr post-infection.	N/A
	(β-d-N4-hydroxycytidine (NHC)[60]	Unknown	IC50 3 μMd,k	N/A	N/A
	Azacytidine[17]	Unknown	IC50 4 μMm,u 86% inhibition at 50 μMd,k	N/A	N/A
	6-azauridine[18]	Unknown	IC50 5 μMn,p and 14 μMm,p 98% inhibition at 80 μMc,k 99% inhibition at 80 μMd,k	N/A	N/A
	Benzoquinoline compounds[61]	Unknown	IC50 0.5–5.6 μMm,u >2 log reduction of viral titer at 1 μMd,k	N/A	N/A
	HSP90 inhibitors (such as geldanamycin, 17AAG and radicicol)[23]	Destabilization of EBOVL	Geldanamycin: IC50 1.6 μMd,k 17AAG: IC50 5.3 μMd,k Radicicol: IC50 1.7 μMd,k	N/A	N/A
	Inhibitors of polyamine biosynthesis (such as DFMO)[63,64]	Defect in EBOV RdRp dependent mRNA accumulation	DFMO: 90% inhibition at 500 μMm,p	N/A	N/A
	Inhibitors of hypusination (such as GC7 and ciclopirox)[63,64]	Ineffective translation of EBOV mRNA	GC7: 85% inhibition at 10 μMm,p Ciclopirox: >2 log reduction of viral titer at 30 μMc,d,o	N/A	N/A
	DHODH inhibitors (such as GSK983 and Brequinar)[65]	Inhibition of de novo pyrimidine synthesis	GSK983: IC50 0.007 μMm,u and <0.02 μMd,f Brequinar: IC50 0.15 μMm,u and 0.1 μMd,f	N/A	N/A
	Inhibitors of VP30 dephosphorylation (such as Okadaic acid (OA) and 1E7–03)[71,72]	Inhibition of viral transcription as phosphorylated VP30 does not participate in transcription	OA: IC50 0.13μM OAm,p >90% inhibition at 0.08 μMd,p,* 1E7–03: 200-fold reduction of viral titerat 10 μMd,k	N/A	N/A
	Tolcapone[77]	Inhibition of NP:NPBP interaction, necessary for polymerase activity	IC50 2 μMq At 10 μM, >100 fold decrease at MOI 0.01 and >5 fold reduction at MOI 2d,k	N/A	N/A
Virus Entry	Compound 7[93]	Direct interaction with GP	IC50 10 μMd,kand 12 μMc,k	N/A	N/A
	LJ001 [94,95]	Inhibition of virus fusion - type II photosensitizer that modifies unsatu rated phospholipids, negatively impacting viral membrane	0.5 μM < IC50 < 1 μMc,d,k	At 20 μM, protects 80% of mice infected with MA-EBOV.	N/A
	Arbidol[97]	Unknown	IC50 2.7 μMd,o	N/A	N/A
	EIPA[79]	Inhibition of macropinocytosis prevents cellular uptake of virus	~50–75% inhibition at 100 μMr,f,k,* ~70% inhibition at 200 μMd,k,*	N/A	N/A
	Latrunculin A[79]	Inhibition of macropinocytosis prevents cellular uptake of virus	~30–65% inhibition at 0.5 μMr,f,k,* ~40% inhibition at 0.5 μMd,k,*	N/A	N/A
	Wortmannin[79]	Inhibition of macropinocytosis prevents cellular uptake of virus	~50% inhibition at 0.1 μMr,f,k,*	N/A	N/A
	Rottlerin[82]	Inhibition of macropinocytosis prevents cellular uptake of virus	>50% inhibition at 2.5 μMr,k	N/A	N/A
	Leupeptin[105]	Inhibition of cysteine-serine protease, inhibits GP proteolysis	>95% inhibition at 10 μMk,s,*	N/A	N/A
	E64, E64a, E64d[84]	Inhibition of cysteine protease, inhibits GP proteolysis	E64d: >90% inhibition at 50 |jMk,s,*	N/A	N/A
	K11777 and derivates[101]	Inhibition of cysteine protease, inhibits GP proteolysis	K11777: 0.87–5.91 nMu,s,t,w Derivatives: 0.1–2.69 nMu,s	N/A	N/A
	CA074[83], CA074Me[84]	Cathepsin B inhibitor	CA074: ~90% inhibition at 10 μMs,k,* >10-fold decrease at 80 μMd,k,* CA074Me: >80% inhibition at 0.5 μMs,k,*	N/A	N/A
	Cathepsin L inhibitor lll[108]	Cathepsin L inhibitor	IC50 7 μMs,u	N/A	N/A
	Aloperine and derivatives[107]	Cathepsin B inhibitor	Derivative 2e: IC50 4.8 μMu,s and 7.1 μMu,t	Aloperine derivative 2e administered half by i.v. (50 μg) and half by i.p.v (50 μg) on day of challenge with pHIV-EBOVGP-Fluc or pHIV-MARVGP-Fluc reduced bioluminescence by 58% 4 days post-infection and 45% 5 days post-infection, respectively.	N/A
	3.0 and 3.47[91,114]	Interacts with NPC1, inhibiting binding of cleaved GP	3.0: 1 μM < IC50 < 10 μMk,s >99% inhibition at 20 μMd,k 3.47: 0.01 μM < IC50 < 0.1 μMk,s	3.47: Mice treated i.p. with 1, 5 or 25 mg/kg daily, showed no protection from MA-EBOV infection.	N/A
	lmipramine[114]	Unknown, mimics NPC1 deficiency	~50% inhibition at 10 μMc,d,x	Mice treated i.p. with 20 mg/kg daily or every other day showed no significant protection from MA-EBOV infection, although lower viral replication at day 3 and 5 was detected.	N/A
	U18666A[90,114]	Unknown, mimics NPC1 deficiency	~99% inhibition at 10 μMs,k	Mice treated i.p with 2 mg/kg daily or every other day showed no significant protection from MA-EBOV infection, although lower viral replication at day 3 was detected.	N/A
	Toremifene[115]	Unknown, off-target effect	IC50 0.973–6.17 μMc,d,e,k	Mice treated i.p. with 60 mg/kg on day 0 and 1 and every other day after showed 50% protection from MA-EBOV infection.	N/A
	Clomiphene[115]	Unknown, off-target effect	IC50 3.83–11.1 μMc,d,e,k	Mice treated i.p. with 60 mg/kg on day 0 and 1 and every other day after showed 90% protection from MA-EBOV infection.	N/A
	Mefloquine[116]	Unknown	IC50 2.73 μMf,r	N/A	N/A
	Posaconazole[116]	Unknown	IC50 7.69 μMf,r	N/A	N/A
	Clarithromycin[116]	Unknown	IC50 4.53 μMf,r	N/A	N/A
	Verapamil[121]	Prevents EBOV escape from endosome	>80% inhibition at 60 μg/mls,t,y	N/A	N/A
	Nimodipine[120]	Prevents EBOV escape from endosome	IC50 ~25 μMd,f,*	N/A	N/A
	Diltiazem[120]	Prevents EBOV escape from endosome	IC50 ~25 μMd,f,*	N/A	N/A
	Tetrandrine[120]	Prevents EBOV escape from endosome	IC50 55 μMd,f	Mice treated i.p. with 30 mg/kg on day 0 and every second day showed 75% protection from MA-EBOV infection. Treatment of 90 mg/kg starting 1 day post-infection protected 50% of mice.	N/A
	Apilimod[123]	Prevents trafficking of incoming virus to NPC1/membrane fusion sites	IC50 0.01–0.14 μMc,d,k,i	N/A	N/A
	Genistein[128]	Unknown	>70% inhibition at 100 μMd,u	N/A	N/A
	Tyrphostin AG1478[128]	Unknown	96–99% inhibition at 100|jMd,u	N/A	N/A
Virus Egress	5539–0062[132]	Inhibits EBOV VP40:tsg101 interaction	>90% inhibition at 100 μMd,r	N/A	N/A
	Compound 1 and derivatives[133]	Inhibits VP40:Nedd4 interaction	Compound 1: 5-fold decrease at 20 μMu,z Compound 4: at 1 μM, 100-foldu,z and 10-foldu,r decrease	N/A	N/A

^aMechanism of Action

^bPhase and NCT identifier of clinical trial and status information from ClinicalTrials.gov

^cMARV

^dEBOV

^eSUDV

^fHela cells

^gIntramuscular route

^hHFF-1, HMVEC-TERT cells

ⁱPrimary macrophages and HUH7 cells

^jIntravenous

^kVero/Vero E6 cells

^lOral route

^mEBOV minigenome assay

ⁿMARV minigenome assay

^oHepG2 cells

^pBSR T7/5 cells

^qFluorescent polarization assay for the interaction of NP and NPBP

^rEBOV VLP

^sEBOV GP pseudotyped virions

^tMARV GP pseudotyped virions

^u293T/293FT cells

^vIntraperitoneal route

^wSUDV, TAFV, RESTV and BDBV GP pseudotyped virions

^xHUVEC cells

^yEAhy cells

^zMARV VLP

^aaMouse-adapted EBOV

^*estimated from figure