Aurelio Zerial

A short lipopeptide, representative of a new family of immunological adjuvants devoid of sugar

Abstract From crude extracts of a Streptomyces strain exhibiting nonspecific immunopotentiating effects, a tetrapeptide was isolated and its structure established as L Ala→D isoGlu→ L,L Dap←Gly. This peptide was devoid of biological activity but its chemical coupling with lauric acid gave a substance endowed with adjuvant and immunostimulating properties. N 2 -[N-(N-lauroyl L alanyl)-gg-D glutamyl]N N 6 -(glycyl) DD, LL 2,6-diaminopimelamic acid prepared by chemical synthesis was shown to be as active, in stimulating antibody production and delayed type hypersensitivity (DTH) reactions in guinea pigs and mice and in enhancing resistance of mice to a bacterial infection, as N-acetylmuramyl-L alanyl-D isoglutamine (muramyl dipeptide, MDP) thus far considered as the minimal adjuvant-active structure of bacterial cell walls. It is concluded that the presence of a sugar moiety (muramic acid) is not an essential prerequisite for immunopotentiating activities and that lipopeptides represent a novel class of potentially useful immunopharmacological agents.

Synergistic activities of type I (α, β) and type II (γ) murine interferons

Type I (alpha, beta) and type II (gamma) murine interferons are able to potentiate each other with respect to the inhibition of encephalomyocarditis (EMC) virus and of herpes simplex virus type 1 (HSV-1) multiplication in a murine cell line (DBT). Examination of two double-stranded RNA-dependent enzymes in DBT cells, the 2-5A synthetase and the 67,000 MW protein phosphokinase indicates that mixed interferon preparations act synergistically at least with respect to an increase in the activity of the former enzyme. The results obtained with gamma interferons of different origin and of different specific activity suggest that interferon itself, rather than the lymphokines present in the interferon preparations, is responsible for the synergistic effect.

Mode of action of the antitumor compound girodazole (RP 49532A, NSC 627434).

Girodazole (RP 49532A) or 3-amino-1-[4-(2 amino-1H-imidazolyl]-propanol, 2HCl is an experimental antitumor compound which inhibits protein synthesis in cell cultures and in cell free systems. The compound has been evaluated for its capacity to inhibit specific assays of initiation, elongation and termination of protein synthesis. Girodazole inhibited the release of nascent peptides from polyribosomes in rabbit reticulocyte lysates indicating that the major effect of the compound is on the protein synthesis termination step.

Antitumor activity and mechanism of action of the marine compound girodazole

SummaryGirodazole, a new marine compound has been isolated from the sponge Pseudaxinyssa cantharella. Girodazole is active in vivo on several murine grafted tumors including leukemias (P388, L1210, i.p./i.p.) and solid tumors (MA 16/C mammary adenocarcinoma, M5076 histiocytosarcoma, s.c./i.v.). In addition, girodazole has identical cytotoxic properties in vitro on P388 and P388/DOX cells and retains antitumor activity in vivo on P388/DOX. Girodazole has a unique chemical structure different from those of known anticancer agents and of new compounds undergoing clinical trials. Biochemical studies indicate that girodazole inhibits protein synthesis during the elongation/termination steps. Toxicological studies have been done in mice and in dogs and did not reveal any major toxic effect which could preclude administration in patients. Girodazole is now undergoing phase I clinical studies.

Inactivation of herpes simplex virus by protein components of bovine neutrophil granules.

From an acid extract of granules of bovine neutrophils we isolated fractions of cationic proteins, exhibiting significant anti-herpesvirus activity at concentrations which were devoid of cytotoxicity and of activity against a picornavirus (rhinovirus). The mechanism of action seems to involve a direct neutralization of the virions. Two antiviral peptides with an approximate MW 7500 were purified to homogeneity by reversed phase high-performance liquid chromatography. Proline and arginine accounted for about 43% and 26-27% of their amino acid residues. One of these peptides (IIIa2 beta) had an MIC of 2 microM.

Selective inhibition of tyrosine protein kinase by a synthetic multisubstrate analog.

Synthetic compounds were designed in an attempt to mimic the possible transition state of tyrosine protein kinases. One representative compound (RP 53801) inhibited the enzyme purified from RSV-transformed cells. A serine/threonine kinase (kinase C) was 45 fold less sensitive. The inhibition was competitive with respect to ATP and noncompetitive with respect to the phosphate acceptor poly glu4-tyr1. The degree of inhibition (IC50 = 22 microM) was however lower than that expected from a transition state analog. The compound was capable of reducing tyrosine protein kinase activity in intact cells with some selectivity at 100 microM.

Synthesis and Biological Evaluation of 3-Deazacytidine and 3-Deazauridine Derivatives

Abstract The synthesis of new 5-and 6- subsituted 3-deazapyrimidine ribonucleosides has been performed by reacting the silylated bases and 1-0-acetyl-2, 3, 5-tri-O-benzoyl-β-D-ribofuranose in dichloroethane in the presence of stannic chloride. None of these compounds exhibited any antiviral activity in vitro against HSV1 and RV31.

Synthesis and experimental anti-tumor activities of 6-alkyl (or aryl) thio 5-deazapteridines

Abstract 6-( p -Bromophenylthio)-5-methyl-2,4,7-triaminopyrido [2,3-d]-pyrimidine was found to be active on P388 and L1210 leukemias while 6-alkylthio derivatives were inactive.

New cyclobutyl analogs of nucleosides. Part 2. Synthesis and antiviral evaluation of 2-amino-7-[3,3-bis (hydroxymethyl)cyclobut-1-yl]-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one and of cyclobutyl analogs of the pyrimidine nucleosides

Abstract The synthesis and antiviral evaluation of a series of 3,3-dihydroxymethyl cyclobutane nucleoside analogs related to the natural anti-HIV nucleoside, oxetanocin A are reported. The different purine and pyrimidine nucleoside analogs described in this paper have been obtained from 1-amino-3,3-dibenzyloxymethylcyclobutane. The compounds were tested against HSV-1, HCMV and HIV-1 in cell cultures, but none of them exhibited activity against these viruses. These results suggest the crucial role of the position of both hydroxymethyl groups in oxetanocin A and oxetanocin G for antiviral activity.

Antiviral activities of 54.247-RP, a carbocyclic analog of 7-deazaguanosine, in cell cultures and animals

Summary The compound (±)-2-amino-3,4-dihydro-7-[(1α, 2α, 3β, 4α)-2,3-dihydroxy-4-(hydroxymethyl)-1-cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidine-4-one, referred to as 54.247-RP, is a new nucleoside analog with anti-herpes properties. At 25 μg/ml (MIC), the antiviral activity appeared to be selective, since the compound inhibited viral DNA synthesis to a greater extent than cellular DNA synthesis. However, at 100 μg/ml, host cell DNA synthesis was also markedly reduced. 54 247-RP, administered intraperitoneally in multiple treatments at doses of 10–20 mg/kg, significantly increased the survival time of mice infected with either HSV 1 or HSV2.