Derivatives of 4‐amino‐3,6‐disulfonato‐1, 8‐naphthalimide inhibit reverse transcriptase and suppress human and feline immunodeficiency virus expression in cultured cells

Abstract

We have developed a series of 4-amino-3,6-disulfonato-1,8-naphthalimide (ADSN) derivatives in an attempt to create nontoxic compounds effective against lentivirus infections. The ADSN derivative Lucifer Yellow CH ([N-(hydra zinocarbonyl)amino]-4-amino-3,6-disulfonato-1,8-naphthalimid e) (LYCH) was chosen as a parent compound because of its low toxicity in vivo and in vitro and its tendency to accumulate in monocyte/macrophages, a major reservoir for lentiviruses in vivo. Several ADSN derivatives inhibited reverse transcriptases (RTs) from human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV). Viral expression in HIV-infected human peripheral blood mononuclear cells was inhibited by noncytotoxic concentrations of two ADSN derivatives, designated A4 (biphenyl-4,4'-dicarboxaldehyde, Lucifer Yellow CH monohydrazone; EC50 = 29 microM after 6 days) and H4 (biphenyl-4,4'-dicarboxaldehyde, Lucifer Yellow CH dihydrazone; EC50 = 5.61 microM). A4 effectively suppressed the expression of FIV in infected Crandall feline kidney fibroblasts (CRFK) at 46.2 microM, reducing the RT levels by 97% after 19 days under conditions allowing direct cell-to-cell transmission of the virus. The viability of drug-treated FIV-infected CRFK cells increased significantly in the presence of A4 relative to the viability of untreated virus-infected cells. In contrast to A4 and H4, LYCH (which lacks the appended aromatic rings characteristic of A4 and H4) had no inhibitory effects on either virus and did not inhibit RT ex vivo. However, flow cytometry studies showed that both A4 and LYCH accumulate in two cell types that can support lentiviral infections: U937 human monocytic leukemic cells that have been induced to differentiate by using tetradecanoyl phorbol acetate, and CRFK cells.

Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen.

“…The purified RT of FIV consists of a single polypeptide of 67,000 M r which is nearly identical to that of HIV RT in template preference, divalent metal ion requirements, and sensitivity to active forms of competitive and noncompetitive inhibitors (156)(157)(158)196) although considerably different from it in the predicted primary sequence (almost 60% divergence [221]). Also, the RNase H activity associated with FIV RT displays ion requirements, substrate preferences, catalytic activity, and sensitivity to polyanionic inhibitors very similar to those of the RNase H associated with HIV RT (38,73).…”

Polyanionic Drugs and Viral Oncogenesis: a Novel Approach to Control Infection, Tumor-associated Inflammation and Angiogenesis

“… alternatively, PS/PSN bind and mask entry receptors for viruses such as the HIV receptor CD4 [ 38 ]. PS/PSN enter the cell and prevent virus replication by inhibiting viral enzymes (such as reverse transcriptase [ 39 , 40 , 41 ], integrase [ 42 ] or the RNAse [ 43 ] of HIV), or viral transactivating factors (such as the transactivating factor Tat of HIV [ 44 ]). natural PS and nutraceuticals enhance inflammatory and immunitary responses to viruses and bacteria with still unknown mechanisms.…”

“…PS/PSN enter the cell and prevent virus replication by inhibiting viral enzymes (such as reverse transcriptase [ 39 , 40 , 41 ], integrase [ 42 ] or the RNAse [ 43 ] of HIV), or viral transactivating factors (such as the transactivating factor Tat of HIV [ 44 ]).…”

Photoinduced electron transfer inN,N-bis(pyridylmethyl)naphthalenediimides: study of their potential as pH chemosensors

“…Most studies in aqueous solution involve the binding to nucleic acids and many of these derivatives are used as DNA intercalators (7)(8)(9)(10)(11). They also show biological applications rely mainly on their pharmacological activity as local anesthetics (12,13), tumoricidals (14,15) and antivirals (16)(17)(18).…”