Guanidinylated 2,5-dideoxystreptamine derivatives as anthrax lethal factor inhibitors

Jiao, Guan-Sheng; Cregar, Lynne; Goldman, Mark E.; Millis, Sherri Z.; Tang, Cho

doi:10.1016/j.bmcl.2005.12.038

Cited by 23 publications

(28 citation statements)

References 35 publications

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“…The guanidinylated 2, 5-dideoxystreptamine compounds were synthesized as previously described [28, 29]. …”

Section: Methodsmentioning

confidence: 99%

“…However, the guanidinylated 2, 5-dideoxystreptamine class of compounds demonstrated bona fide and potent NS3 protease inhibition against the DENV(1-4) and WNV NS3 proteases. These compounds have been previously demonstrated to inhibit furin and anthrax lethal factor (LF) proteases [28, 29] and are shown here to be competitive inhibitors of WNV and DENV NS2b/NS3 proteases from all four serotypes.…”

Section: Introductionmentioning

confidence: 97%

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Small Molecule Pan-Dengue and West Nile Virus NS3 Protease Inhibitors

Cregar-Hernandez

Jiao

Johnson

et al. 2011

Antivir Chem Chemother

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Background Dengue fever, dengue hemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV) and are an increasing global health risk. The related West Nile Virus (WNV) causes significant morbidity and mortality as well and continues to be a threat in endemic areas. Currently no FDA approved vaccines or therapeutics are available to prevent or treat any of these infections. Like the other members of the Flaviviridae family, DENV and WNV encode a protease (NS3) which is essential for viral replication and therefore is a promising target for developing therapies to treat dengue and West Nile infections. Methods Flaviviral protease inhibitors were identified and biologically characterized for mechanism of inhibition and DENV anti-viral activity. Results A guanidinylated 2, 5-dideoxystreptamine class of compounds was identified that competitively inhibited the NS3 protease from DENV(1-4) and WNV with IC50 values in the 1-70 μM range. Cytotoxicity was low; however, antiviral activity versus DENV-2 on VERO cells was not detectable. Conclusions This class of compounds is the first to demonstrate competitive pan-dengue and WNV NS3 protease inhibition and, given the sequence conservation among flavivirus NS3 proteins, suggests that developing a pan-dengue or possibly pan-flavivirus therapeutic is feasible.

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“…The guanidinylated 2, 5-dideoxystreptamine compounds were synthesized as previously described [28, 29]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Small Molecule Pan-Dengue and West Nile Virus NS3 Protease Inhibitors

Cregar-Hernandez

Jiao

Johnson

et al. 2011

Antivir Chem Chemother

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“…As outlined in Fig. 2A, the di-aryl substituted compounds 1b-1m (see Table 1 for structures) were synthesized as described (34). In a similar manner, the tri-aryl substituted compounds 1n and 1o (Table 1) were prepared by the S N Ar coupling of three equivalents of nitro-substituted aryl halides with mono-Cbz-protected compound 7 as the key step (Fig.…”

Section: Synthesis Of Guanidinylated Aryl 25-dideoxystreptamine Derimentioning

confidence: 99%

“…We set out to test the hypothesis by using our in-house collection of guanidinylated 2,5-dideoxystreptamine derivatives that had been shown to exhibit inhibition of anthrax LF (34). The in vitro biochemical assay results revealed that the set of guanidinylated mono-aryl substituted 2,5-dideoxystreptamine derivatives (Fig.…”

Section: Identification Of Furin-inhibitory Lead Compound 1amentioning

confidence: 99%

Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine

Jiao¹,

Cregar

Wang

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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108

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Furin plays a crucial role in embryogenesis and homeostasis and in diseases such as Alzheimer's disease, cancer, and viral and bacterial infections. Thus, inhibition of furin may provide a feasible and promising approach for therapeutic intervention of furin-mediated disease mechanisms. Here, we report on a class of small molecule furin inhibitors based on 2,5-dideoxystreptamine. Derivatization of 2,5-dideoxystreptamine by the addition of guanidinylated aryl groups yielded a set of furin inhibitors with nanomolar range potency against furin when assayed in a biochemical cleavage assay. Moreover, a subset of these furin inhibitors protected RAW 264.7 macrophage cells from toxicity caused by furin-dependent processing of anthrax protective antigen. These inhibitors were found to behave as competitive inhibitors of furin and to be relatively specific for furin. Molecular modeling revealed that these inhibitors may target the active site of furin as they showed site occupancy similar to the alkylating inhibitor decanoyl-Arg-Val-LysArg-CH 2Cl. The compounds presented here are bona fide synthetic small molecule furin inhibitors that exhibit potency in the nanomolar range, suggesting that they may serve as valuable tools for studying furin action and potential therapeutics agents for furindependent diseases.serine endoprotease ͉ prohormone ͉ proprotein convertase F urin is a membrane-anchored, calcium-dependent serine endoprotease and is expressed in all tissues and cell lines examined (1-3). It is the first and, so far, the best-characterized member of the mammalian subtilisin-like family of prohormone/proprotein convertases (PCs), which convert precursors of many secreted proteins and peptide hormones into their biologically active forms (1-3). Furin is predominantly localized in the trans-Golgi network and cycles between this compartment, the cell surface, and the endosomes (2, 4). Hence, furin is able to access and efficiently process a diverse spectrum of substrates including growth factors, receptors, serum proteins, matrix metalloproteinases, viral envelope glycoproteins, and bacterial toxins, typically at sites with the consensus sequence Arg-Xaa-Lys/Arg-Arg 2 (2).Although furin plays an essential role in embryogenesis and homeostasis, this endoprotease has also been implicated in the neurodegeneration associated with Alzheimer's disease, and tumor metastasis and the activation and virulence of many bacterial and viral pathogens (2). It has been demonstrated that furin inhibitors modulate tumor growth (5) and attenuate the toxicity of anthrax (6) and Pseudomonas aeruginosa (7) toxins and cytomegalovirus (8) in cell culture and animal models. Therefore, furin inhibitors hold great promise as potential therapeutic agents for treating furinmediated diseases and viral and bacterial infections, particularly for short-term therapy.To date, most furin inhibitors reported in the literature have been proteins (9-19) or peptides (20-24), which show excellent potency against furin, and largely mimic the substrate in bindi...

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“…A representative peptidomimetic hydroxamic acid is compound 8 . 9 Not shown in Figure 2 are miscellaneous additional reported inhibitors of lethal factor protease, including guanidinylated derivatives of neamine 40 and streptamine, 41 aminoglycosides, 42 cationic polyamines, 43 and inhibitors from green tea. 44 …”

Section: Introductionmentioning

confidence: 99%