Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a 3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor

Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B′, CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor

In vitro and in vivo study of an albumin-binding prodrug of doxorubicin that is cleaved by cathepsin B

PURPOSE: This study was designed to evaluate the in vitro and in vivo antitumor activity of an albumin-binding prodrug of doxorubicin 1 which incorporates a maleimide moiety and a para-aminobenzyloxycarbonyl (PABC) spacer coupled to the dipeptide Phe-Lys that is cleaved by cathepsin B. METHODS: Cleavage of the albumin conjugate was studied with cathepsin B and in homogenates of MDA-MB 435 tumors. For in vivo studies, nude mice were injected with (a) glucose buffer, (b) doxorubicin (2 x 8 mg/kg, i.v, on days 10 and 17), or (c) compound 1 (3 x 24 mg/kg doxorubicin equivalent, on days 10, 17 and 24). RESULTS: Prodrug 1 once bound to albumin was effectively cleaved by cathepsin B and in tumor homogenates releasing doxorubicin. A cytotoxicity assay of the albumin conjugate of 1 in two human tumor cell lines showed that doxorubicin was ~6 times more active than the conjugate. In contrast, in an in vivo study, the prodrug exhibited superior antitumor activity (T/C 15%) compared to doxorubicin (T/C 49%) in an equitoxic comparison. CONCLUSIONS: The cathepsin B cleavable spacer Phe-Lys-PABC incorporated in an albumin-binding prodrug is an effective way to increase the therapeutic index of doxorubicin

Comparative evaluation of the biological properties of reducible and acid-sensitive folate prodrugs of a highly potent doxorubicin derivative

Two new water-soluble folate receptor-targeted drug conjugates that contain the highly active doxorubicin derivative N-(5,5-diacetoxybut-1-yl)doxorubicin were designed and evaluated for their biological activity against folate receptor positive tumours. The prodrugs were designed to contain an acid-sensitive hydrazone bond KO019 or in addition a disulphide bond KO013 in order to elucidate the importance of the pre-determined breaking point for their in vitro and in vivo properties. Fluorescence microscopy studies confirmed higher uptake of the prodrugs in folate receptor positive KB cells than in the folate receptor negative A549 lung cancer cells. In subsequent in vivo studies in the folate receptor positive KB xenograft model, KO019 was as active as the free drug but significantly less toxic when dosed at twice the dose of the free drug whereas KO013 showed no anticancer efficacy. As an explanation, we could show by HPLC that the prodrug KO013 that additionally contains a disulphide bond undergoes rapid disulphide exchange in murine plasma in the order of 40% after 5h at 37°C in contrast to KO019 which was essentially stable after a 5h incubation

Liberating methodologies and Nakba studies: Palestinian history and memory from below as sites of lifelong learning

Historians too often construct frameworks and methodologies which obfuscate social, economic and political oppression. This article explores new historical methodologies that can represent oppressed and marginalised groups in Palestine. In particular the article focuses on the role of indigenous history and memory in critical learning and shaping individual and collective identity in Palestine. It further argues that Palestinian memories ‘from below’ since the Nakba have played a major positive role in the recovery from the traumatic catastrophe and the reconstruction of Palestinian identity. The article critiques the manipulation of collective memory by social, political and economic elites and top-down nationalist approaches. It argues that reconfigured popular memories can be liberating and empowering for embattled Palestinians. The article also calls for the establishment of an interdisciplinary subfield of Nakba Studies that would bring together historians, social memory and cultural theorists, postcolonial scholars and scholars of trauma studies with the aim of documenting and studying the embattled social memory of Palestine as a site of lifelong learning and empowerment