Ana Teran

STRUCTURE AND ABSOLUTE STEREOCHEMISTRY OF HIV-1 INTEGRASE INHIBITOR INTEGRIC ACID. A NOVEL EREMOPHILANE SESQUITERPENOID PRODUCED BY A XYLARIA SP.

Abstract HIV-1 integrase is critical for viral replication and is absent in the host, and therefore is a potential target for the development of non-toxic antiviral therapy. From the screening of natural product libraries we have discovered integric acid, a novel eremophilane sesquiterpenoid, from a Xylaria sp. It inhibited 3′ -end processing, strand transfer and disintegration reactions catalyzed by HIV-1 integrase with IC50 values of 3–10 μM. The isolation, structure elucidation, relative, and absolute stereochemistry of integric acid are described.

Four novel bis-(naphtho-γ-pyrones) isolated from Fusarium species as inhibitors of HIV-1 integrase

Abstract Integration of viral DNA into host cell DNA is an essential step in retroviral (HIV-1) replication and is catalyzed by HIV-1 integrase. HIV-1 integrase is a novel therapeutic target and is the focus of efforts to identify effective inhibitors that will prevent/or cure HIV infections. Four novel naphtho-γ-pyrones, belonging to the chaetochromin and ustilaginoidin family, were discovered as inhibitors of HIV-1 integrase from the screening of fungal extracts using a recombinant in vitro assay. These compounds inhibit both the coupled and strand transfer activity of HIV-1 integrase with IC 50 values of 1–3 and 4–12 μM, respectively. The discovery, structure elucidation, chemical modification and the structure–activity relationship of these compounds are described.

Integrastatins: structure and HIV-1 integrase inhibitory activities of two novel racemic tetracyclic aromatic heterocycles produced by two fungal species

Abstract Integrastatins are two novel aromatic natural products derived from fungal fermentations who possess a novel [6/6/6/6]-ring system and are racemic despite having two asymmetric centers. These compounds inhibited the strand transfer reaction of HIV-1 integrase with IC 50 values of 1.1–2.5 μM.

Biogeography and relatedness of Nodulisporium strains producing nodulisporic acid

Nodulisporic acid, a novel indole terpene with insecticidal properties, was first isolated from a fermentation broth of an endophytic Nodulisporium sp. Following an extensive culture screening effort, fermentations of 12 other strains of Nodulisporium also yielded nodulisporic acid. These strains came from a variety of environmental substrata collected from seven tropical regions in four continents. Cul- tural characteristics and microscopic features show that all the nodulisporic acid-producing Nodulispor- ium strains are morphologically very similar. AP-PCR and sequencing of the rDNA region consisting of the two internal transcribed spacers and the 5.8S gene revealed that the isolates were distributed into three groups, according to the length of the ITS1. The two groups with the longest sequences were not distin- guishable, based on nucleotide divergence data cal- culated from the common region of ITS1. The group of isolates with shorter sequences showed lower ho- mology with the other groups in the ITS1 region, but those strains could not be distinguished from the oth- er groups, according to ITS2 sequences. These data suggest that the nodulisporic acid producing isolates are very closely related and may constitute a single species, although divided into populations showing some degree of genetic differentiation. Comparison of the sequences obtained in this work with sequenc- es from other xylariaceous fungi with Nodulisporium- type anamorphs failed in determining the teleo- morph of the nodulisporic acid-producing Nodulis- porium species. However, it revealed that these iso- lates constitute a monophyletic group, clearly

Discovery, structure and HIV-1 integrase inhibitory activities of integracins, novel dimeric alkyl aromatics from Cytonaema sp.

Abstract Integrase is a critical viral enzyme for HIV-1 replication and is a novel target for therapeutic intervention against HIV infections. Integracins A–C are three novel dimeric alkyl aromatic inhibitors of HIV-1 integrase discovered from the screening of fungal extracts using an in vitro assay. These compounds inhibit both coupled and strand transfer activity of HIV-1 integrase with IC50 values of 3.2–6.1 and 17–88 μM, respectively. The discovery, structure and activity of these compounds are described.

Potent and Selective Peptide Agonists of α‐Melanocyte Stimulating Hormone (αMSH) Action at Human Melanocortin Receptor 5; their Synthesis and Biological Evaluation in vitro

Melanocortin receptors (MC1‐5R) and their endogenous ligands (melanocyte‐stimulating hormones and adrenocorticotropic hormone) are involved in many physiological processes in humans. Of those receptors, the actions of MC5R are the least understood despite its broad presence in the numerous peripheral tissues and brain. In this study, we describe synthesis and pharmacological properties in vitro (receptor‐binding affinity and agonist activity) of several cyclic analogs of αMSH which are potent agonists at hMC5R (EC50 below 1 nm) and of enhanced receptor subtype selectivity (more than 2000‐fold versus hMC1b,3R and about 70‐ to 200‐fold versus hMC4R). These compounds are analogs of Ac‐Nle4‐cyclo[Asp5–His6‐D‐Nal(2′)7–Pip8–Trp9–Lys10]–NH2 (Pip: pipecolic acid) in which His6 has been replaced with sterically hindered amino acids. They may be useful tools in the elucidation of the MC5R role in skin disorders and in immunomodulatory and in anti‐inflammatory actions of αMSH.