[Frontiers in Bioscience 3, d1241-1252, December 1, 1998]

	[Frontiers in Bioscience 3, d1241-1252, December 1, 1998] Reprints PubMed CAVEAT LECTOR
	INHIBITION OF INTERNAL ENTRY SITE (IRES)-MEDIATED TRANSLATION BY A SMALL YEAST RNA: A NOVEL STRATEGY TO BLOCK HEPATITIS C VIRUS PROTEIN SYNTHESIS Saumitra Das¹, Michael Ott², Akemi Yamane¹, Arun Venkatesan¹, Sanjeev Gupta² and Asim Dasgupta¹ Department of Microbiology, Molecular Genetics and Immunolog, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747¹, ²Department of Medicine, Albert Einstein, College of Medicine of Yeshiva University, Bronx, New York 10461-1602 Received 9/18/98 Accepted 9/23/98 5. PRESPECTIVE Since the naturally occurring small yeast RNA (I-RNA) appears to block translation of the viral RNA but does not significantly affect cellular capped mRNA translation, it would be interesting to determine whether I-RNA or it’s derivatives can be used as an antiviral agent against viruses that exclusively use IRES-mediated translation for synthesis of viral proteins. The inhibitor RNA does not act as an antisense RNA, rather it interacts with cellular protein factors that are necessary for IRES-mediated translation. We strongly believe that the I-RNA can fold into a stable secondary structure which mimics part of the viral 5´ -UTR RNA and thus compete for protein binding. Thus, determination of its 3-dimensional structure might lead to design of a more stable derivative of I-RNA or small molecules which would be biologically more effective in inhibition of viral RNA translation. The knowledge gained by studying I-RNA/cellular protein interaction would help in understanding the mechanism of IRES mediated translation. What is the normal function of I-RNA in yeast? Some of the yeast genes are reported to be internally initiated. It is possible I-RNA regulates the expression of these genes by inhibition of internal initiation of translation. The normal function of I-RNA in yeast is not known. However , sequence spanning the active site of I-RNA have been found to be highly homologous with an yeast chromosome 3 fragment (in the strain used in the database). I-RNA was originally isolated from the S. cerevisiae ABYS1 strain. The yeast genome database search suggests that a chromosome 12 fragment could code for the leader sequence (1-15 nt.), whereas the activity domain of I-RNA (15-60 nt.) has been identified in a chromosome 3 fragment. Further experimentation is necessary to understand whether this discontinuity in sequence is due to trans splicing or simply strain variation. Future studies would be directed towards identification of the common factors involved in IRES mediated translation in different systems, evaluate the potential of the I-RNA as a general inhibitor of IRES mediated translation and eventually design an effective antiviral agent targeting this unique mechanism of viral RNA translation.

[Frontiers in Bioscience 3, d1241-1252, December 1, 1998]
Reprints
PubMed
CAVEAT LECTOR

INHIBITION OF INTERNAL ENTRY SITE (IRES)-MEDIATED TRANSLATION BY A SMALL YEAST RNA: A NOVEL STRATEGY TO BLOCK HEPATITIS C VIRUS PROTEIN SYNTHESIS

Saumitra Das¹, Michael Ott², Akemi Yamane¹, Arun Venkatesan¹, Sanjeev Gupta² and Asim Dasgupta¹

Department of Microbiology, Molecular Genetics and Immunolog, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747¹, ²Department of Medicine, Albert Einstein, College of Medicine of Yeshiva University, Bronx, New York 10461-1602

Received 9/18/98 Accepted 9/23/98

5. PRESPECTIVE

Since the naturally occurring small yeast RNA (I-RNA) appears to block translation of the viral RNA but does not significantly affect cellular capped mRNA translation, it would be interesting to determine whether I-RNA or it’s derivatives can be used as an antiviral agent against viruses that exclusively use IRES-mediated translation for synthesis of viral proteins. The inhibitor RNA does not act as an antisense RNA, rather it interacts with cellular protein factors that are necessary for IRES-mediated translation. We strongly believe that the I-RNA can fold into a stable secondary structure which mimics part of the viral 5´ -UTR RNA and thus compete for protein binding. Thus, determination of its 3-dimensional structure might lead to design of a more stable derivative of I-RNA or small molecules which would be biologically more effective in inhibition of viral RNA translation. The knowledge gained by studying I-RNA/cellular protein interaction would help in understanding the mechanism of IRES mediated translation.

What is the normal function of I-RNA in yeast? Some of the yeast genes are reported to be internally initiated. It is possible I-RNA regulates the expression of these genes by inhibition of internal initiation of translation. The normal function of I-RNA in yeast is not known. However , sequence spanning the active site of I-RNA have been found to be highly homologous with an yeast chromosome 3 fragment (in the strain used in the database). I-RNA was originally isolated from the S. cerevisiae ABYS1 strain. The yeast genome database search suggests that a chromosome 12 fragment could code for the leader sequence (1-15 nt.), whereas the activity domain of I-RNA (15-60 nt.) has been identified in a chromosome 3 fragment. Further experimentation is necessary to understand whether this discontinuity in sequence is due to trans splicing or simply strain variation.

Future studies would be directed towards identification of the common factors involved in IRES mediated translation in different systems, evaluate the potential of the I-RNA as a general inhibitor of IRES mediated translation and eventually design an effective antiviral agent targeting this unique mechanism of viral RNA translation.