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Previous studies have shown that acylated plasma and milk proteins with increased negative charge, derived from various animal and human sources, are potent anti-HIV compounds. The antiviral effects seemed to correlate positively with the number of negative charges introduced into the various polypeptides: proteins with a high content of basic amino acids in which all of the available epsilonNH2 groups were anionized yielded the most potent anti-HIV compounds. It remained unclear however whether the total net negative charge of the various derivatized proteins, or rather the charge density on the protein backbone, is essential for the observed anti-HIV activity. Earlier studies have shown that acylated albumins preferentially block the process of HIV/cell fusion through binding to the HIV envelope proteins gp120 and gp41 as well as to the cell surface of the HIV target cells. Some of these polyanionic proteins have been shown to interfere also with the gp120-CD4 mediated virus/cell binding. The relative contribution of these effects to the anti-HIV activity may depend both on the total negative charge introduced as well as the hydrophobicity of the acylating reagent added to the particular proteins. In this study we show that the higher the charge density of the derivatized proteins, the more potent their HIV replication inhibiting effects are. In contrast, the addition of positive charge to the studied plasma and milk proteins through amination resulted in a reduced anti-HIV activity but a clearly increased anti-HCMV activity, with IC50 values in the low micromolar concentration range. Interestingly, native lactoferrin (Lf) was antivirally active against both HIV and HCMV. Acylation or amination of Lf increased the anti-HIV and anti-HCMV activity, respectively. The N-terminal portion of Lf appeared essential for its anti-HCMV effect: N-terminal deletion variants of human Lf were less active against HCMV. Circular dichroism of the modified proteins showed that the secondary structure of the tested proteins was only moderately influenced by acylation and/or covalent attachment of drugs, making these (derivatized) proteins useful candidates as antiviral agents and/or intrinsically active drug carriers. The relatively simple chemical derivatization as well as the abundant sources of blood plasma and milk proteins provides attractive opportunities for the preparation of potent and relatively cheap antiviral agents for systemic or local applications.

With the aim to improve and extend the antiviral activity of the antiherpic drug penciclovir, to a wider spectrum of viruses, we have synthesized and characterized new binary and ternary complexes of Pd(II) of formulae cis-(pen)2PdCl2 and cis-[(nucl)2Pd(pen)2]Cl, where nucl guanosine, inosine, cytidine or penciclovir. The characterization was mainly based on IR and 1H NMR spectroscopy, and the results showed that in all prepared complexes, penciclovir coordinates to the metal through N7. The far-i.r, spectrum of the complex cis-(pen)2PdCl2 conf’mned the cis- geometry around Pd(II). All the prepared complexes were markedly active against HSV-1 and HSV-2 strains, but not against thymidine kinase-deficient HSV-1 strains.

Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the treatment of HPV-associated diseases. We have evaluated the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV), ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant mycophenolic acid (MPA) on the proliferation of human cervical keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). In vitro incubation of these cell lines with ANPs resulted in a concentration- and time-dependent inhibition of cell proliferation. This inhibitory effect was most striking for HPMPC. The 50% inhibitory concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to 0.6-2 microg/ml at day 7. When the IC50 values of the ANPs for the various HPV-harboring cells were compared with those for primary human keratinocytes isolated from normal cervix, HPMPC emerged as the most selective ANP, with a selectivity index (SI) in the range of 15-42. When IC50 values as a function of time were determined for several tumor cell lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs again showed an antiproliferative effect as a function of time, although of a lower extent (5- to 25-fold decrease in the IC50 values between days 3 and 7) than for the HPV-positive cells. Treatment of SV40- and adenovirus-transformed cells with ANPs resulted in the inhibition of cell proliferation as a function of time, similar to that observed with HPV-positive cells, HPMPC and cHPMPC being the most potent antiproliferative agents. These results suggest that the antiproliferative activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may be explained, at least in part, by a specific inhibitory effect on rapidly proliferating cells, and the presence of the HPV genome might enhance the sensitivity of cells to HPMPC due to interactions of the viral-transforming proteins with products of the tumor suppressor genes.

Abstract No antiviral activity or cytotoxic effects are detected for the novel tiazofurin aza‐analogue (XI) as well as its hydrazide and hydroxylamide analogues.