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Biomedical subjects

G Witherell

Publications and source records attributed to G Witherell.

5 recordsLinked to original sources
PubMed2001

The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5' secondary structure.

Eukaryotic initiation factor (elF) 4A functions as a subunit of the initiation factor complex elF4F, which mediates the binding of mRNA to the ribosome. elF4A possesses ATPase and RNA helicase activities and is the prototype for a large family of putative RNA helicases (the DEAD box family). It is thought that the function of elF4A during translation initiation is to unwind the mRNA secondary structure in the 5' UTR to facilitate ribosome binding. However, the evidence to support this hypothesis is rather indirect, and it was reported that elF4A is also required for the translation of mRNAs possessing minimal 5' UTR secondary structure. Were this hypothesis correct, the requirement for elF4A should correlate with the degree of mRNA secondary structure. To test this hypothesis, the effect of a dominant-negative mutant of mammalian elF4A on translation of mRNAs with various degrees of secondary structure was studied in vitro. Here, we show that mRNAs containing stable secondary structure in the 5' untranslated region are more susceptible to inhibition by the elF4A mutant. The mutant protein also strongly inhibits translation from several picornavirus internal ribosome entry sites (IRES), although to different extents. UV crosslinking of elF4F subunits and elF4B to the mRNA cap structure is dramatically reduced by the elF4A mutant and RNA secondary structure. Finally, the elF4A mutant forms a more stable complex with elF4G, as compared to the wild-type elF4A, thus explaining the mechanism by which substoichiometric amounts of mutant elF4A inhibit translation.

5' Untranslated Regions↗
PubMed2001

BMS-232632 (Novartis/Bristol-Myers Squibb).

BMS-232632, an azapeptide HIV protease inhibitor, is in development by Bristol-Myers Squibb (BMS), under license from Novartis, as a potential treatment for HIV/AIDS [248556]. Early preclinical work was carried out by Novartis [248556]. BMS-232632 was developed as part of a series of compounds (as CGP-73547) and evaluated against drug-resistant strains of HIV; the compounds in this series belong to a series of azadipeptide analogs and are bis(L-tert-leucine) derivatives that exhibit good antiviral activity and satisfactory pharmacokinetic profiles [297907]. Novartis subsequently discontinued evaluation of the compound in November 1999 [347827]. Phase II trials had already begun by July 1999 [334335] and BMS expects NDA filing to take place in 2001 [358937]. Use of BMS-232632 in combination with other antiretroviral agents has demonstrated that it may be used in combination with a variety of nucleoside analogs and protease inhibitors [298464]. It is thought to have a genotypic resistance profile that differs from that of other protease inhibitors [302157]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2001. The analysts predicted peak sales would occur in 2007, with sales of $500 million in the US and $300 million in the rest of the world at that time [319225].

Administration, Oral↗
PubMed2000

AG-7088 Pfizer.

Pfizer (formerly Agouron) is developing AG-7088, a peptide aldehyde that targets the human rhinovirus (HRV) 3C proteinase enzyme and has potential for the treatment of the common cold. A phase II efficacy study has been completed in healthy patients infected with the virus [318668] and in November 1999, Agouron initiated a large, double-blind, placebo-controlled trial in the US, in individuals within 36 h of experiencing cold symptoms [346362]. AG-7088 is derived from AG-6084, the development of which has been discontinued. In order to develop human rhinovirus 3C protease inhibitors with improved pharmacological properties, Agouron replaced the backbone amide moiety of the series which yielded AG-6084, with a ketomethylene isostere. Such compounds displayed slightly reduced anti-3CP inhibitory activity, but improved antiviral properties, due to increased cell membrane permeability [324627]. Compounds in which P1 lactam moieties were incorporated in lieu of an L-glutamine residue displayed significantly increased 3CP inhibition activity and improved antirhinoviral properties relative to the corresponding molecules. Of this series, AG-7088 was the most potent inhibitor [324635]. In May 2000, Merrill Lynch predicted that phase III trials would begin in the first half of 2000 and that US filing would take place in the second half of 2001 [375962].

Antiviral Agents↗
PubMed1994

Interaction of poliovirus with its cell surface binding site.

The interaction of poliovirus with its cellular binding sites was characterized by using a receptor-excess silicon oil partition assay. Poliovirus type 1 Mahoney [PV1(M)] binding to HeLa cells fits a theoretical simple bimolecular noncooperative binding curve with an equilibrium dissociation constant (Kd) of 4.3 x 10(7) cells.ml-1 at 4 degrees, or 2.1 x 10(-10) M, assuming 3000 virus binding sites/cell. The association rate of complex formation was measured to be 3.6 x 10(-9) ml.cell-1.min-1 (7.2 x 10(8) M-1.min-1) and the dissociation rate calculated to be 1.5 x 10(-1) min-1, giving the complex a half-life of 4.5 min. The equilibrium dissociation constant, association rate, and dissociation rate were also measured for the binding of the attenuated poliovirus type 3 Sabin strain [PV3(S)] to HeLa cells. PV3(S) bound HeLa cells with a Kd of 3.3 x 10(7) cells.ml-1 (1.6 x 10(-10) M), an association rate of 4.1 x 10(-9) ml.cell-1.min-1 (8.2 x 10(8) M-1.min-1), and a dissociation rate calculated to be 1.4 x 10(-1) min-1, giving the complex a half-life of 5.1 min. Thus the virulent and avirulent strains of poliovirus bind HeLa cells with nearly identical binding constants and rate constants. Equilibrium binding constants for PV1(M) to various other cell types varied from a high affinity of 4.1 x 10(6) cells.ml-1 for JA-1 cells to a low affinity of 7 x 10(7) cells.ml-1 for NGP cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗